While many breast cancer patients experience "normal" distress, there is a subset who experience clinically significant depression. We examined the current knowledge about the prevalence, impact and treatment of major depression in women with breast cancer. We reviewed the evidence for the prevalence of depression in women with breast cancer from the last 20 years and summarized the medical literature on the pharmacology and psychotherapy of depression in this population. Despite evidence that depression significantly impacts quality of life in breast cancer patients, few studies focus on the epidemiology and treatment of major depression. Treatment studies have focused on distress and mixed depressive states, with resulting lack of replicable studies showing treatment efficacy. Potential biological and psychosocial determinants of major depression following breast cancer are discussed in a proposed model. The need for further research on the epidemiology and treatment of major depression in this population is proposed. Major depression is a frequent but underrecognized and undertreated condition among breast cancer patients, which causes amplification of physical symptoms, increased functional impairment and poor treatment adherence. More research on the epidemiology and treatment of major depression in this population is needed.