<jats:title>Abstract</jats:title> <jats:p>MicroRNAs (miRNAs) are a class of powerful post-transcriptional regulators implicated in the control of diverse biological processes, including regulation of hematopoiesis and the immune response. To define the biological functions of miR-142, which is specifically and abundantly expressed in immune cells, we created a mouse line with targeted deletion of this gene. Our analysis of miR-142-/- mice revealed a critical role for this miRNA in the development and homeostasis of lymphocytes. Marginal zone B cells expand in the knockout spleen, while the number of T and B1 B cells in the periphery is reduced. Abnormal development of hematopoietic lineages in miR-142-/- animals is accompanied by a profound immunodeficiency, manifested by hypoimmunoglobulinemia and failure to mount a productive immune response to soluble antigens and virus. miR-142-/- B cells express elevated levels of BAFF receptor (BAFF-R) and as a result proliferate more robustly in response to BAFF stimulation. Lowering the BAFF-R gene dose in miR-142-/- mice rescued the B cell expansion defect, suggesting that BAFF-R is a bona fide miR-142 target through which it controls B cell homeostasis. Collectively, our results uncover miR-142 as an essential regulator of lymphocyte ontogenesis and suggest that lesions in this miRNA gene may lead to primary immunodeficiency.</jats:p>