Lymphocyte differentiation from haematopoietic stem cells (HSCs) is a multi-step process in which lineage fate choices are made at crucial branch points. Plasticity of common precursors is evidenced by presence of transcriptionally favourable chromatin structures at several lineage-specific loci, making them poised for further priming and regulation. Down the differentiation tree, the interplay between lineage-specific networks of transcription factors and epigenetic modifications gradually decreases the multipotency ability of precursors and increases the compromise of cells within a particular lineage. The maintenance of a cell-specific phenotype is the result of sustained gene expression programs resulting from activation of lineage-specific and repression of lineage-discrepant loci. Theperipheral functional specialisation oflymphocytes requires furtherplasticity, to allow differentiation onto short term effectors cells, orlong term memory circulating and resident cells. Impaired differentiation of lymphocytes or deregulated or unbalanced production of certain lymphocytes subsets underlies thepathogenesis of lymphoproliferation, autoimmunity and possibly immunodeficiency. Understanding epigenetic mechanisms governing lymphocyte differentiation would allow future therapeutic interventions to prevent aberrant deviations or promote beneficial cell populations.