CD40-mediated cancer therapy has been under development since it became clear that CD40 plays a profound role in the stimulation of adaptive immune responses. Further, CD40 signaling on tumor cells may lead to growth arrest or even apoptosis that improves therapy outcome. The therapeutic window is appealing since the immune system is selective and normal cells do not apoptose upon CD40 signaling. AdCD40L is an adenoviral-based immunostimulatory gene therapy under evaluation for its efficacy to treat cancer. Because of its nature, the adenoviral backbone will stimulate TLRs while CD40L potentiates the shifts toward Th1 type of immunity. AdCD40L has shown efficacy in various murine models, and safety studies have been performed on dog patients and in human clinical trials. AdCD40L has been used for both ex vivo gene modification of tumor cell vaccines as well as for direct intratumoral injections. Lately, an oncolytic vector has been used to further increase the eradication of solid tumors that as a consequence further boosts the release of tumor antigens and creates danger signaling in the tumor micro milieu. This review discusses the currently unfolding mechanisms of action of AdCD40L gene therapy and its possibilities to reach clinical care.