Advances in immuno-oncology over the last several years have led to FDA approvals of novel agents. As our understanding of immune response and its checkpoints has evolved, further advances have been made in treatment for several cancer types. To predict a response to immunotherapy, the initial biomarkers used were expression of the PD-1 receptor and PD-L1, as assessed by immunohistochemistry. More recently, predictive biomarkers have included microsatellite instability, DNA mismatch repair, and tumor mutational burden. Although these markers may be clinically relevant in predicting an immunotherapy response, cancer immunotherapy fails some patients. Improved understanding of the human immune system is necessary, as is a careful evaluation of the methods used to predict and assess response to immuno-oncology treatments. With the application of therapeutic immune-modulating agents, more comprehensive assays, and associated bioinformatics tools to accurately assess the tumor microenvironment, we may better predict responses to immuno-oncology agents and the ever-increasing complexity of their clinical use.