Recent research indicates that subtle differences may exist in the symptom profile of male and female depression. The aim of this review is to examine male/female differences in depressive psychopathology in light of the latest research findings and discuss whether these differences might suggest the need for gender specific treatments. Multiple searches using Medline (1985-2008) were carried out. Additional searches were made using the reference lists of published papers and chapters from books. Differences exist in the clinical profile and comorbidity of male and female individuals with depression. Subtle genetic differences, the role of hormones, the role of preexisting anxiety, and personality differences are some of the factors responsible for these findings. These differences imply that different treatment options should be available for males and females suffering from depression. The available data suggest that clinically relevant differences in depressive symptom profile and the underlying pathophysiology between genders in depression do exist. The identification of distinct endophenotypes for major depression, will not only improve our understanding of the disease, but will also contribute to more specific treatment strategies.