Agents targeting programmed death-1 (PD-1) and its ligand (PD-L1), cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), and—more recently—next-generation checkpoints, such as lymphocyte activation gene-3 (LAG-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and B and T lymphocyte attenuator (BTLA), have demonstrated the capacity to unshackle anti-tumor immunity and to reshape therapeutic algorithms across melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and numerous other tumor types. The gene discussed is BTLA; the disease is renal cell carcinoma.