Affinity maturation and terminal differentiation of B-cells via the germinal center reaction is a complex multi-step process controlled by transcription factors that induce or suppress large dynamic transcriptional programs. This occurs via the recruitment of co-activator or co-repressor complexes that epigenetically regulate gene expression by post-translationally modifying histones and/or remodeling chromatin structure. B-cell-intrinsic developmental programs both regulate and respond to interactions with other cells in the germinal center that provide survival and differentiation signals, such as T follicular helper cells and follicular dendritic cells. Epigenetic and transcriptional programs that naturally occur during B-cell development are hijacked in B-cell lymphoma by genetic alterations that directly or indirectly change the function of transcription factors and/or chromatin modifying genes. These in turn skew differentiation towards the tumor cell-of-origin and alter interactions between lymphoma B-cells and other cells within the microenvironment. Understanding the mechanisms by which genetic alterations perturb epigenetic and transcriptional programs regulating B-cell development and immune interactions may identify opportunities to target these programs using epigenetic modifying agents. Here, we discuss recently published studies centered on follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) within the context of prior knowledge, and highlight how these insights have informed potential avenues for rational therapeutic interventions.