Neoantigen is a patient-specific tumor antigen resulted from mutations during oncogenesis. Emerging data suggested that immune responsiveness against neoantigens correlated with the success of clinical tumor immunotherapies. Nowadays, the majority of studies on neoantigens have focused on MHC class I restricted antigens recognized by CD8+ T cells. With improved understanding of the underlying principles of tumor biology and immunology, increasing emphasis has been put on CD4+ T cells and MHC class II restricted antigens. MHC class II restricted neoantigen has the potential to be a promising target of tumor immunotherapy, although the limited comprehension and technical difficulties need to be overcome before being applied into clinical practice. This review discussed the immunologic mechanism, screening technique, clinical application, limitations and prospectives of MHC class II restricted neoantigens in tumor immunotherapy.