Chronic lymphocytic leukemia (CLL) is the most common leukemia among adult population in western country. In the last decade, several findings have substantially revolutionized the old concept that CLL is a disease originating from mature, not-dividing cell with indolent clinical course. Notably, next generation sequencing (NGS) has contributed to deepen the knowledge of the cellular networks that imply the onset and the progression of CLL. Among genetic aberrations that are recurrently observed in B-cells from patients with CLL, microRNA deregulation represented the first epigenetic mechanism that has been identified. Through epigenetic mechanism they can modulate gene expression and interfere with cellular pathways that are involved in cell cycle, apoptosis and B-cell receptor (BCR) activation. Although few studies have shown the prognostic and predictive value of microRNA expression levels, their validation within prospective clinical trials is warranted.