Adoption of maize (Zea mays L.) hybrids with enhanced drought/heat/low N stress tolerance and increasing the application of N fertilizer have both been proposed as potential solutions for Sub-saharan Africa (SSA)’s food insecurity. Neither solution, however, has been able to increase grain yield in SSA at the same rate seen in other parts of the world as drought/heat/low N stress are often not the only yield-limiting factors in SSA. The primary objectives of this study were to determine what stresses are limiting grain yield response to N fertilizer, to evaluate differences among hybrids in terms of their relative stress tolerance and N use efficiency (NUE), and to quantify the impact of N fertilizer on improving grain yield and mitigating other stresses and soil N depletion. From 2010 to 2015, six maize hybrids, three with high anticipated stress tolerance (HAT) and three with low anticipated stress tolerance (LAT) were grown in a continuous maize cropping system at four N rates in Embu, Kenya (drought + nutrient stress), in Harare, Zimbabwe (nutrient stress), and in Kiboko, Kenya (heat + nutrient stress) for a total of 5 to 9 seasons. Nitrogen rates were 0, 30, 60, and 90 kg N ha-1 in Embu and 0, 40, 80, and 160 kg N ha-1 in Harare and Kiboko. Grain yield was measured every season and anthesis-silking interval (ASI) in most seasons. During at least one season in each site, grain and stover samples collected at harvest were analyzed for biomass response to N and essential macro/micro-nutrients. Post-harvest of the final season, soil was sampled to a depth of 90 cm in each plot at 5 depth increments (0-15, 15-30, 30-45, 45-60, 60-90 cm) and analyzed for general soil characteristics (pH, bulk density, OM, etc.), inorganic and total N, and plant essential macro/micro-nutrients. We found that grain yields of all hybrids increased when N fertilizer was applied and the agronomic optimal N rate either exceeded the N rates applied or fell between the highest 2 applied N rates. The NUE in Kiboko (\u3e40 kg grain kg-1N applied), however, was more than two-fold the NUE in Embu and Harare (~20 kg kg-1). There were negative correlations between grain yield and ASI (r=0.46 in Embu, r=0.64 in Kiboko), signifying that there was moderate drought stress in Embu and severe heat stress in Kiboko. The high soil N levels in Embu and application of N fertilizer in Kiboko appeared to have mitigated some drought/heat stress. In spite of there being anticipated differences in stress tolerance among hybrids, in this study, no hybrid consistently ranked higher or lower than other hybrids in terms of grain yield or NUE at any site. Soil K availability was limited by drought in Embu. In both Embu and Kiboko, the ratio of total plant N to total plant K did not decrease with N rate as it did in Harare, suggesting that the impact of higher N rates on K uptake is greater in drought/heat stressed sites than in non-drought/heat stressed sites. Two hybrids in Harare, TH127618 (a HAT hybrid) and S513 (a LAT hybrid) were apparently able to take up enough K to avoid deficiency, but the other Harare hybrids were found to be potentially K deficient at maturity. There was a high risk of Mn toxicity in Embu in all hybrids, but one hybrid (Duma43, a LAT hybrid) took up relatively low amounts of Mn and, thus, may have had some degree of Mn toxicity tolerance. Otherwise, there were no differences among hybrids within any site in terms of their apparent nutrient sufficiency status at maturity. Hybrids in both Embu and Kiboko, however, differed in their stover nutrient accumulation. DK8031, a HAT hybrid in Embu, and H513, a LAT hybrid in Kiboko, had the greatest capacity among hybrids in their respective sites to deplete soil nutrient pools via stover-enhanced nutrient mining. While a 15N sub-study found that only 13-25% of the N applied was recovered by the plants, all hybrids at most N rates took up more N than was applied, resulting in a negative N balance of as low as 103 kg N ha-1 in a season. The N balance calculation is likely to have underestimated actual N depletion as more N may have been lost from the rooting profile via runoff or leaching in all sites. Embu’s acidic, clay rich soils, however, sequestered more N than the other sites, reducing the loss of N via leaching. The N internal efficiencies (NIE) of the hybrids (grain yield produced per unit N taken up) were calculated at each N rate. Hybrids in all sites had low NIE (37 to 47 kg grain kg N-1 in Embu, 33 to 36 kg grain kg N-1 in Harare, and 34 to 52 kg grain kg N-1 in Kiboko) due to limited access to soil N and/or non-N stress induced reductions in N uptake and remobilization. Non-N soil nutrient interactions limited the uptake of P in Embu and of P, Cu, S, and Zn in Harare. While low soil pH and high soil amorphous Fe levels in Embu and Harare limited P availability and uptake, similar interactions between P and Zn in the Kiboko’s alkaline soil did not lead to corresponding deficiencies. The uptake of Cu appeared to suppress the uptake of Zn and vice versa. Similarly, the uptake of S and Cu were inversely linked. The availability of P and Cu were related to the degree to which each was stratified in the soil. Although the addition of N fertilizer did not eliminate nutrient deficiency, it did increase overall uptake of P and S in all sites and Cu and Zn in Harare and Kiboko on a total content basis. Grain P concentrations increased as the N rate increased in Embu and Kiboko, although not enough for hybrids to escape P deficiency in Embu. Grain Zn concentration also increased with higher N rates at Embu. This increased plant uptake of non-N nutrients at higher N rates did not result in measurable depletion of the corresponding soil nutrient pools with the exception of soil available P in Harare and Kiboko. This study found that an in-depth soil analysis can explain why stress tolerant hybrid performance and response to N is low in SSA. Drought stress in Embu and heat stress in Kiboko, coupled with non-N nutrient stress in Embu and Harare and below-replacement N fertilizer rates limited NIE in all sites and NUE in Embu and Harare. While the 15N sub-study found that only a small fraction of the fertilizer applied was recovered by the plant, the plants took up more total N than was applied in all sites at most N rates, resulting in soil N depletion. The idealized fertilizer N balance calculation likely underestimated actual N depletion; the extent to which soil N was depleted was dependent on soil texture and pH. The application of N fertilizer is a potential strategy for agronomic biofortification by increasing the uptake of P, S, Zn, and Cu (content) in maize. In summary, the co-existence of multiple stresses was found to limit the performance of single-stress tolerant hybrids, but the addition of N fertilizer was found to mitigate the impact of non-N stresses on hybrid performance