Cancer research has seen unprecedented advances over the past several years, with tremendous insights gained into mechanisms of response and resistance to cancer therapy. Central to this has been our understanding of crosstalk between the tumor and the microenvironment, with the recognition that complex interactions exist between tumor cells, stromal cells, overall host immunity, and the environment surrounding the host. This is perhaps best exemplified in cancer immunotherapy, where numerous studies across cancer types have illuminated our understanding of the genomic and immune factors that shape responses to therapy. In addition to their individual contributions, it is now clear that there is a complex interplay between genomic/epigenomic alterations and tumor immune responses that impact cellular plasticity and therapeutic responses. In addition to this, it is also now apparent that significant heterogeneity exists within tumors-both at the level of genomic mutations as well as tumor immune responses-thus contributing to heterogeneous clinical responses. Beyond the tumor microenvironment, overall host immunity plays a major role in mediating clinical responses. The gut microbiome plays a central role, with recent evidence revealing that the gut microbiome influences the overall immune set-point, through diverse effects on local and systemic inflammatory processes. Indeed, quantifiable differences in the gut microbiome have been associated with disease and treatment outcomes in patients and pre-clinical models, though precise mechanisms of microbiome-immune interactions are yet to be elucidated. Complexities are discussed herein, with a discussion of each of these variables as they relate to treatment response.