Over the past 20 years, tuberculosis incidence in southern Africa has increased at an alarming rate, fuelled primarily by the human immunodeficiency virus epidemic. The emerging prevalence of diabetes mellitus in the region represents a new threat to tuberculosis control. The intersecting double burden is a cause for concern since diabetes mellitus increases the risk of tuberculosis and results in poor treatment outcomes. This review article discusses the evidence of a causal association between these two conditions, and examines the numerous clinical challenges that relate to tuberculosis and diabetes mellitus co-management. Diabetes is associated with a more advanced age and body weight in patients with tuberculosis, although not with a specific clinical presentation of tuberculosis. Rifampicin adversely alters glycaemic control by lowering the concentrations of most oral antidiabetic drugs. Poor glycaemic control, possibly exacerbated by tuberculosis and anti-tuberculous therapy, is an important contributing factor to tuberculosis case fatality and relapse. Clinicians need to be aware of these clinical and pharmacological challenges when co-managing these complex diseases.Keywords: diabetes, tuberculosis, rifampicin, co-management, southern Afric