Therapeutic cancer vaccines have undergone a resurgence in the past decade. A better understanding of the breadth of tumour-associated antigens, the native immune response and development of novel technologies for antigen delivery has facilitated improved vaccine design. The goal of therapeutic cancer vaccines is to induce tumour regression, eradicate minimal residual disease, establish lasting antitumour memory and avoid non-specific or adverse reactions. However, tumour-induced immunosuppression and immunoresistance pose significant challenges to achieving this goal. In this Review, we deliberate on how to improve and expand the antigen repertoire for vaccines, consider developments in vaccine platforms and explore antigen-agnostic in situ vaccines. Furthermore, we summarize the reasons for failure of cancer vaccines in the past and provide an overview of various mechanisms of resistance posed by the tumour. Finally, we propose strategies for combining suitable vaccine platforms with novel immunomodulatory approaches and standard-of-care treatments for overcoming tumour resistance and enhancing clinical efficacy.