This chapter provides a comprehensive overview of the genetic and epigenetic mechanisms regulating immune checkpoint expression, with a particular focus on PD-1 as a model system. It begins by introducing the concept of T cell exhaustion and its relevance in chronic infections and cancer. The chapter then explores the structure of the PD-1 gene (PDCD1) and its regulatory regions, providing a foundation for understanding transcriptional control. A significant portion is dedicated to exploring the roles of various transcription factors in modulating PD-1 expression, including NFAT, Blimp-1, Notch, TOX, and STATs. Each factor’s mechanism of action and its impact on checkpoint expression are discussed in detail. The chapter then transitions to epigenetic regulation, covering both DNA methylation and histone modifications. It examines how these epigenetic marks influence checkpoint gene accessibility and expression, and how they contribute to the establishment and maintenance of the exhausted T cell phenotype. The chapter also touches on the interplay between transcription factors and epigenetic modifiers in shaping the overall regulatory landscape. It also explores the epigenetic differences between exhausted, effector, and memory T cells to highlight the unique epigenetic profile of exhausted cells. The implications of these findings for immunotherapy, particularly in the context of checkpoint blockade resistance, are discussed. Finally, the chapter concludes by outlining future research directions and potential therapeutic strategies based on manipulating the genetic and epigenetic regulation of immune checkpoints.