Cancer immunotherapy has come of age with the advent of immune checkpoint inhibitors. In this article we review how agonists for receptors of the innate immune system, the Toll-like receptors and the RIG-I-like receptors, impact anticancer immune responses. Treatment with these agonists enhances the activity of anticancer effector cells, such as cytotoxic T cells and NK cells, and at the same time blocks the activity of immunosuppressive cell types such as regulatory T cells and myeloid-derived suppressor cells. These compounds also impact the recruitment of immune cells to the tumor. The phenomena of pattern-recognition receptor tolerance and reprogramming and their implications for immunotherapy are discussed. Finally, novel delivery systems that target the immune-stimulating drugs to the tumor or the tumor-draining lymph nodes to enhance their efficacy and safety are presented.