Monoclonal B lymphocytosis (MBL) is a frequent phenomenon in the general population. Despite a phenotype similar to chronic lymphocytic leukemia (CLL), the possibility exists that most cases are not necessarily a pre-leukemic condition. This is suggested by the fact that MBL is at least 100 times more frequent than CLL and the diagnosis of CLL is not an inevitable fate, even among MBL cases with lymphocytosis, where it occurs only in 1.1% of the cases per year. The high incidence of MBL, if coupled with the possibility of evolution into a frank leukemic state, poses evident clinical and health system concerns. MBL in the general population usually accounts for a very low number of all circulating B-cells, being <10% of all B lymphocytes. This creates the need for a better characterisation of MBL at molecular level, aiming to identify biological features that may define which cases are more likely to progress towards clinically overt CLL. This approach should also help to avoid unnecessary and prolonged follow-ups in all individuals carrying MBL, excluding those who are extremely unlikely to develop CLL.