Cancer immunotherapy aims to use the immune system of the body for improved therapeutic effects on tumors. Currently, one of the more encouraging interventions under evaluation involves the use of immune checkpoint blockade, which offers longer benefit periods and greater patient tolerance than previous interventions for solid malignancies. Nevertheless, a majority of patients never respond or gradually acquire resistance; hence, a suboptimal effect of the therapy ensues. Resistance to such treatments may arise from tumor-specific factors, host factors, and environmental influences. There is growing evidence that the gut microbiome is an important modulator not only of the efficacy of these treatments but also of toxicities. Current studies are focused on the identification of key microbial profiles from both preclinical and clinical samples associated with immunotherapeutic response and antitumor activities. Elucidation of this complex interaction may provide ways to modulate gut microbial communities to improve patient outcomes. The current review addresses the components responsible for resistance against immune checkpoint inhibitors and highlights the crucial linkage between gut microbiome-immune interactions. We further summarize some recent clinical findings and explore prospective avenues for research in this evolving area of cancer treatment.