Lymphocyte differentiation and identity are controlled by signals in the microenvironment that ultimately mediate gene expression in the nucleus. Although much focus has centered on the strategic and often unique roles transcription factors play within lymphocyte subsets, it is increasingly clear that another level of molecular regulation is crucial for regulating gene expression programs. In particular, epigenetic regulation is critical for appropriately regulated temporal and cell-type-specific gene expression during immune responses. As such, mutations in epigenetic modifiers are linked with lymphomagenesis. Furthermore, certain infections can remodel the epigenome in host cells, either through the microenvironment or by directly co-opting host epigenetic mechanisms, leading to inappropriate gene expression and/or ineffective cellular behavior. This review will focus on how histone modifications and DNA methylation, and the enzymes that regulate the epigenome, underpin lymphocyte differentiation and function in health and disease.