Human mesenchymal stem cells (hMSCs) consist of cells that can differentiate into mesenchymal tissues, including osteoblasts, adipocytes and chondrocytes. hMSCs constitute a particular stem cell niche in the stromal compartment of the bone marrow, and play a role in maintaining the normal function of haematopoietic stem cells. Furthermore, hMSCs localise to solid tumours, and can modulate cancer cell function through secretion of paracrine signals. While hMSCs, either in the bone marrow, or in the microenvironment of a tumour, will be targeted by DNA damaging agents used in cancer therapy, the response of the hMSC population to DNA damage is not well understood. As progenitor cells, genomic DNA damage to hMSCs during cancer therapy could generate a population of surviving cells that can go on to give rise to secondary tumours. A better understanding of the response of hMSCs to DNA damage could provide new insights into the effects of cancer treatments, as well as into the development of treatment-associated secondary cancers. This article reviews the relationship of hMSCs to cancer, with a focus on the response of hMSCs to DNA damaging agents.