CD40L-based therapy is currently under intensive investigation for its potent anti-tumor effects in experimental animal models of cancer as well as in Phase I clinical trials. CD40L is one of the strongest inducers of Th1 responses although it stimulates both innate and adaptive immunity. The molecule is normally expressed by activated immune cells such as T helper cells that act on dendritic cells to induce their maturation and capability of activating tumor-reactive T cells. Moreover, recent findings implicate that CD40L stimulation abrogates the suppressive effect of T regulatory cells. Interestingly, while being an activator of immune cells, CD40L has been shown to directly induce apoptosis in tumor cells by mechanisms only beginning to emerge. These two major effector mechanisms synergize to combat tumor growth. Optimal use of this multipotent molecule might therefore result in effective immunotherapy of cancer. CD40L can be administered to patients as soluble protein trimers. To achieve membrane-bound expression, viral vectors can be used to transfer CD40L cDNA into 1) tumor cells ex vivo for creating CD40L-expressing tumor vaccines, 2) ex vivo cultured dendritic cells for cell therapy, and 3) tumor nodules in situ. CD40L substitutes such as CD40-directed agonistic antibodies have been evaluated with interesting results in experimental models. In this survey, different types and mechanisms of CD40Lbased therapy will be discussed from bench to bedside.