The success of immune checkpoint inhibitor therapy in lung cancer, both in squamous and nonsquamous non-small cell carcinoma, has led to US Food and Drug Administration approval for 2 medications that have as part of their prescribing information an associated immunohistochemistry-based companion or complementary diagnostic test for programmed death ligand-1 (PD-L1). The intense interest in drug development in this area has resulted in additional agents with associated diagnostics looming on the horizon in 2016. In the era of precision medicine, the paradigm of paired molecular target and molecular test, which serves as a model of oncogenic mutation-driven cancer therapy, is challenged by the proliferation of immunohistochemistry-based tests with different antibodies, instruments, and scoring. The difficulty inherent to targeted therapy aimed at a moving target is discussed, as well as the emerging challenges to pathologists and oncologists who seek to optimize care in this complex therapeutic arena.