Background/Objectives: Advances in understanding immune checkpoint pathways and tumor immune biology have enabled the development of immune checkpoint inhibitors (ICIs), particularly targeting the PD-1/PD-L1 axis, which has transformed cancer immu-notherapy. Despite their success across multiple tumor types, including melanoma, non-small-cell lung cancer, and gastrointestinal malignancies, variability in patient re-sponse, immune-related adverse events (irAEs), and resistance mechanisms remain sig-nificant. This review aims to evaluate clinical pharmacology, mechanisms of action, re-sistance pathways, and pharmacogenomic influences shaping interindividual responses to ICIs. Methods: This comprehensive review synthesizes current literature on FDA-approved ICIs, exploring their clinical use, underlying biological mechanisms, and emerging pharmacogenomic data. It also assesses key biomarkers such as tumor muta-tional burden (TMB), microsatellite instability (MSI), HLA diversity, and epigenetic factors influencing ICI efficacy and safety. Results: We identify key mechanisms contributing to ICI resistance, including T cell dysfunction, altered antigen presentation, and immuno-suppressive tumor microenvironment components. Furthermore, we highlight promising pharmacogenomic findings, including single-nucleotide polymorphisms (SNPs) in PD-1/PD-L1 and immune-regulatory genes, offering predictive and prognostic utility. Variability in PD-L1 expression and the role of epigenetic modifications are also ad-dressed as challenges in treatment optimization. Conclusions: Interindividual variability in ICI response underscores the need for biomarker-driven strategies. By integrating pharmacogenomic insights with clinical pharmacology, future approaches may support more personalized and effective use of ICIs. Combination therapies and novel modalities hold promise for overcoming resistance, enhancing therapeutic efficacy, and enabling precision oncology.