Over the past 25 years, epidemiological and clinical studies have linked psychological factors such as stress, chronic depression, and lack of social support to the incidence and progression of cancer. Although the mechanisms underlying these observations are not completely understood, recent molecular and animal studies have begun to identify specific signaling pathways that could explain the impact of neuroendocrine effects on tumor growth and metastasis. This review will highlight the importance of known clinical, molecular, and cellular processes with regard to the neuroendocrine stress effects on tumor biology and discuss possible behavioral and pharmacological interventions to ameliorate these effects and ultimately improve cancer outcomes.