When facing comorbidity, effects of medicating one disorder on the other disease is a key question for the clinician. As depression influences both development and outcome of oncological diseases, early diagnosis and therapy, primarily with antidepressants, is of paramount importance. This paper gives a survey on the effects of antidepressants on comorbid mood disorders, on the course of cancerous diseases and on the tumor itself. Response to therapy is similar for patients with comorbid and primary depression, just as there is no significant difference in tolerability. Early studies have shown that antidepressants increase the risk of tumor development, have negative effects on the outcome of oncological diseases and even increase mortality. However, recent epidemiological and clinical studies show opposing results and demonstrate beneficial action of antidepressants on various oncological diseases such as glióma and hepatocellular cancer. Like any drug, antidepressants have effects not only on targets in the brain but also on other organs, hence on tumor tissues as well. Latest preclinical studies demonstrate that certain antidepressants facilitate apoptosis, autophagy of tumor cells and potentiate the efficacy of anticancer agents acting as chemosensitizers. Direct and indirect antitumor effects of antidepressants are proven, however, their clinical use requires further studies focusing on the specificity of agents on different tumor types.