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CD40–CD40L interactions play an important role in the generation of humoral and cell-mediated immunity. Due to the expression of CD40 on antigen presenting cells, it has become an attractive target for immunotherapy against cancer. Recent studies have focused on using CD40 stimulation as an adjuvant, and in conjunction with cytokines and other factors to elicit antitumor responses. However, due to the pleiotropic effects of CD40 stimulation, and the wide array of cell types upon which it is expressed, new studies are also focusing on the nonimmune related consequences of systemic and local CD40 stimulation. Systemic administration of immunotherapy regimens containing CD40 stimulation via soluble ligands and agonist antibodies has been associated with some toxicities, and direct stimulation of CD40 expressed on various malignancies and vascular endothelium has elucidated a possible role for CD40 in the transformation and progression of malignancies. This review focuses on the role of CD40 stimulation in the generation of innate and adaptive antitumor responses, as well as the direct effects of CD40 stimulation on tumor survival, death, and angiogenesis.