Posttranslational modifications of histone proteins represent a fundamental means to define distinctive epigenetic states and regulate gene expression during development and differentiation. Aberrations in various chromatin-modulation pathways are commonly used by tumors to initiate and maintain oncogenesis, including lymphomagenesis. Recently, increasing evidence has demonstrated that polycomb group (PcG) proteins, a subset of histone-modifying enzymes known to be crucial for B-cell maturation and differentiation, play a central role in malignant transformation of B cells. PcG hyperactivity in B-cell lymphomas is caused by overexpression or recurrent mutations of PcG genes and deregulation of microRNAs (miRNAs) or transcription factors such as c-MYC, which regulate PcG expression. Interplays of PcG and miRNA deregulations often establish a vicious signal-amplification loop in lymphoma associated with adverse clinical outcomes. Importantly, aberrant enzymatic activities associated with polycomb deregulation, notably those caused by EZH2 gain-of-function mutations, have provided a rationale for developing small-molecule inhibitors as novel therapies. In this review, we summarize our current understanding of PcG-mediated gene silencing, interplays of PcG with other epigenetic regulators such as miRNAs during B-cell differentiation and lymphomagenesis, and recent advancements in targeted strategies against PcG as promising therapeutics for B-cell malignancies.