The goal of precision immunotherapy is to direct a patient's T cell response against the immunogenic mutations expressed on their tumors. Most immunotherapy approaches to-date have focused on MHC class I-restricted peptide epitopes by which cytotoxic CD8⁺ T lymphocytes (CTL) can directly recognize tumor cells. This strategy largely overlooks the critical role of MHC class II-restricted CD4⁺ T cells as both positive regulators of CTL and other effector cell types, and as direct effectors of antitumor immunity. In this review, we will discuss the role of neoantigen specific CD4⁺ T cells in cancer immunotherapy and how existing treatment modalities may be leveraged to engage this important T cell subset.