The bone marrow microenvironment is home to haematopoietic and mesenchymal cell populations that regulate bone turnover through complex interactions. The high proliferative capacity of these cell populations makes them susceptible to damage and injury, which alters the steady-state function of the bone marrow environment. Following cancer chemotherapy, irradiation and long-term glucocorticoid use, a fatty marrow cavity is typically observed, whereby reduced bone and increased fat formation of marrow stromal progenitor cells often results in increased marrow fat, reduced bone mass and increased fracture risk. Although the underlying mechanisms remain to be clearly elucidated, recent investigations have suggested a switch in lineage commitment of bone marrow mesenchymal stem cells down the adipogenic lineage at the expense of osteogenic differentiation, following damage caused by treatment regimens. As the Wnt/β-catenin signaling pathway has been recognized as the key mechanism regulating stromal commitment, its involvement in the osteogenic and adipogenic lineage commitment switch under damaging conditions has been of great interest. This chapter will review the effects of chemotherapy treatment regimens on commitment to the adipogenic and osteogenic lineages of bone marrow stromal progenitor cells. It will also summarize the Wnt/β-catenin signaling pathway and its role in stromal cell lineage commitment and recovery after damage, as well as its potential use as a therapeutic target.