Tamoxifen is widely used for the treatment of breast cancer. While it is generally well tolerated, clinically relevant depression may be a common side effect. This article reviews reports of depression associated with tamoxifen and considers the specific qualities of tamoxifen that may account for depressive symptomatology. A multitude of factors may be responsible for depression in the breast cancer patient such as adjuvant therapy, stage of treatment, and poor body image. Tamoxifen distinguishes itself due to its potential activity at the neuroendocrine level. Antagonist qualities of tamoxifen may block the neuroprotective effects of estrogen. This may result in down-regulation of neurotransmitters associated with mood regulation such as serotonin and norepinephrine. Additional research into the mechanism of tamoxifen-associated depression is needed. As the use of tamoxifen increases, it will be essential to consider the potential side effect of depression, which in itself may alter immune function and overall survival. The risk and benefits of tamoxifen must be carefully weighed and depressive symptoms should be monitored and treated in women receiving tamoxifen therapy.