Immunotherapy using chimeric antigen receptor (CAR)-engineered T-cells has proven transformative in the management of selected haematological malignancies. However, it remains much less effective against solid tumours. In part, this is due to heterogeneity of antigen expression and the profoundly immunosuppressive nature of the tumour microenvironment. Epitope spreading entails the diversification of the immune response, allowing primed T-cells to target additional epitopes within the same antigen (intra-molecular) or a distinct antigen (inter-molecular; also known as antigen spreading). The occurrence of epitope spreading has been described in some immune competent mouse models and clinical studies of CAR T-cell immunotherapy. Interferon γ and granulocyte macrophage colony-stimulating factor have been implicated in this process through the recruitment and activation of antigen-presenting cells and T-cells. However, epitope spreading is not universally observed following CAR T-cell immunotherapy, prompting efforts to boost this. Accordingly, CAR T-cells have been engineered to produce a range of immunostimulatory factors. Moreover, alternative host cells including natural killer (NK) T-cells and macrophages have been proposed to more efficiently support epitope spreading. Additionally, a range of combination treatment strategies have been evaluated. Thus, CAR T-cells have been co-administered with vaccines, radiotherapy, stimulator of interferon genes (STING) agonists, tumour-tropic bacteria, oncolytic viruses and lipid nanoparticles. Effective harnessing of epitope spreading offers the potential to overcome key limitations of CAR T-cell therapy for solid tumours, nullifying the impact of tumour antigen loss and heterogeneity. However, it may trigger clinically significant autoimmunity in some patients.