The recent emergence of immune checkpoint inhibitors for cancer therapy has created much excitement among cancer patients, drug and diagnostic developers, and health care professionals. This is due largely to the dramatic and sustained responses among some advanced cancers that were previously refractory to therapy. Unfortunately, these responses are difficult to predict, so the goal of the right drug for the right patient at the right time remains elusive. This is in part due to the complexity of the tumor immune microenvironment and its role in drug efficacy. The application of biomarkers to pathologic specimens to predict responses to therapy remains one of the key roles for pathologists in precision medicine. For the new immune checkpoint inhibitors, the emerging class of biomarkers revolves around the immunohistochemical detection of the drug target (or its ligand), programmed cell death ligand 1, on tumor cells or associated immune cells. The diagnostic terrain is already complex because of the involvement of different technology platforms, antibody clones, scoring systems, and indications for their use. The application of these biomarkers to cytologic specimens is critical because the current drug indications are for advanced-stage cancers that are often sampled by minimally invasive cytologic means rather than surgical resection. This review summarizes the current state of biomarkers for immune checkpoint inhibitors with an emphasis on the opportunities for and threats to cytologic samples. Cancer Cytopathol 2018;126:11-9. © 2017 American Cancer Society.