Considerable research in the field of immunotherapy for melanoma has demonstrated that this tumor type can be responsive to therapeutic immune activation strategies. In early clinical trials, vaccine strategies using dendritic cells (DCs) and adenovirus (Ad) vectors (AdVs) were safe and immunogenic, and induced clinical responses in a minority of patients. Research from the past several years has yielded an improved mechanistic understanding of DC biology, AdV effects on DCs and the crosstalk that occurs between antigen-loaded DCs and specific lymphocyte subsets. This knowledge base is being combined with technological advances in cytokine delivery, AdV design and in vivo DC targeting. These developments are leading to novel AdV-transduced DC-based therapeutic modalities that may further advance melanoma immunotherapy. Interactions between AdVs and DCs, initial clinical trial results, and new developments in DC engineering and in AdV biology are reviewed.