B-cell chronic lymphocytic leukemia (CLL) is the most frequent human leukemia and it occurs in two forms, indolent and aggressive. Although clinical features and genetic abnormalities in CLL are well documented, molecular details underlying the disease are still under investigation.MicroRNAs are small noncoding RNAs involved in a variety of cellular processes and expressed in a tissue-specific manner. MicroRNAs have the ability to regulate gene expression. In physiological conditions, microRNAs act as gene expression controllers by targeting the mRNA or inhibiting its translation. Their deregulation can lead to an alteration of the expression level of many genes which can induce the development or promote the progression of tumors.In CLL, microRNAs can function as oncogenes, tumor suppressor genes, and/or can be used as markers for disease onset/progression. For example, in indolent CLL, 13q14 deletions targeting miR-15/16 initiate the disease, while in aggressive CLL miR-181 targets the critical TCL1 oncogene and can also be used as a progression marker.Here we discuss the foremost findings about the role of microRNAs in CLL pathogenesis, and how this knowledge can be used to identify new approaches to treat CLL.