Monoclonal B-cell lymphocytosis (MBL), a newly recognized entity found in approximately 3% of normal persons, precedes chronic lymphocytic leukemia. However, MBLs progress into overt malignancy only in a very minor portion of cases, thus raising the clinical concern of whether and how we can discriminate at diagnosis which rare cases will evolve into a fully fledged tumor. Understanding the molecular/biologic features underlying the risk of progression may significantly modify our strategies for correctly managing B-cell premalignant states. MBL cells bear the same chromosomal abnormalities of chronic lymphocytic leukemia. Genome-wide sequencing and animal models indicate that genetic abnormalities disrupting the control of cell growth and survival cooperate with microenvironment-triggered events, mainly represented by antigen-mediated B-cell receptor and coreceptor stimulation, to trigger and fuel clonal expansion. The initial functional activation of survival/proliferation pathways may later become subsidized by autonomous genetic abnormalities (eg, a single mutation) affecting the same or parallel critical signaling pathway(s).