Resistance to cancer therapy remains a major challenge in clinical oncology. Although the initial treatment phase is often successful, eventual resistance, characterized by tumour relapse or spread, is discouraging. The majority of studies devoted to investigating the basis of resistance have focused on tumour-related changes that contribute to therapy resistance and tumour aggressiveness. However, over the last decade, the diverse roles of various host cells in promoting therapy resistance have become more appreciated. A growing body of evidence demonstrates that cancer therapy can induce host-mediated local and systemic responses, many of which shift the delicate balance within the tumour microenvironment, ultimately facilitating or supporting tumour progression. In this Review, recent advances in understanding how the host response to different cancer therapies may promote therapy resistance are discussed, with a focus on therapy-induced immunological, angiogenic and metastatic effects. Also summarized is the potential of evaluating the host response to cancer therapy in an era of precision medicine in oncology.