Early attempts to harness the immune system against cancer met with disappointment, in large part, due to limited understanding of the immune system and specifically of T cell biology. The first cancer immunotherapies focused predominantly on approaches to turn “on” the immune response. The “on” switches consisted of T cell receptor binding to major histocompatibility complex (MHC) plus antigen and CD28 binding to its ligand B7, which is expressed on antigen presenting cells such as dendritic cells. The method used to turn “on” T cells was to either engage the T cell receptor with antigenic stimuli, such as peptide vaccines, or engage CD28 for T cell costimulation, for example, with activated dendritic cells. The field had not yet envisioned that T cells also had “off” switches. The concept of blocking inhibitory signals, termed checkpoints, was a major shift that jumpstarted the cancer immunotherapy field. Immune checkpoint therapy (ICT) together with other approaches to modulate tumor-immune interactions such as constitutive androstane receptor (CAR) T cells, cytokine-based therapies, and vaccines are the theme of this cancer immunotherapy special issue.