Immunotherapy is rapidly expanding the treatment landscape available to cancer patients. As the field continues to develop and translate novel and combinatorial agents, there is an increasing need to identify predictive and/or prognostic biomarkers that can guide personalized cancer treatment recommendations. One of the most prominent predictive biomarkers of response to immune checkpoint inhibitors (ICIs) is programmed cell death ligand 1 (PD-L1) expression within the tumor immune microenvironment (TME) which has resulted in the United States Food and Drug Administration (FDA) approval of a companion diagnostic for ICIs across several tumor types. The identification of a biomarker that enriches for cancer patients who may derive clinical benefit from a particular therapy has become an increasingly important component of drug development and the FDA approval process in order to improve cancer care delivery while simultaneously containing health care costs. However, this paradigm shift brings to the forefront several challenges with implementing routine biomarker testing. We discuss the growing role of biomarkers in guiding personalized cancer care as well as the gap, and potential opportunities, for advancing innovative technologies to support the rapidly evolving paradigms of cancer treatment.