AbstractEffective regulation of immune-cell activation is critical for ensuring that the immune response, and inflammation generated for the purpose of pathogen elimination, are limited in space and time to minimize tissue damage. Autoimmune disease can occur when immunoreceptor signaling is dysregulated, leading to unrestrained inflammation and organ damage. Conversely, tumors can coopt the tissue healing and immunosuppressive functions of hematopoietic cells to promote metastasis and evade therapy. The Src-family kinase Lyn is an essential regulator of immunoreceptor signaling, initiating both proinflammatory and suppressive signaling pathways in myeloid immune cells (eg, neutrophils, dendritic cells, monocytes, macrophages) and in B lymphocytes. Defects in Lyn signaling are implicated in autoimmune disease, but mechanisms by which Lyn, expressed along with a battery of other Src-family kinases, may uniquely direct both positive and negative signaling remain incompletely defined. This review describes our current understanding of the activating and inhibitory contributions of Lyn to immunoreceptor signaling and how these processes contribute to myeloid and B-cell function. We also highlight recent work suggesting that the 2 proteins generated by alternative splicing of lyn, LynA and LynB, differentially regulate both immune and cancer-cell signaling. These principles may also extend to other Lyn-expressing cells, such as neuronal and endocrine cells. Unraveling the common and cell-specific aspects of Lyn function could lead to new approaches to therapeutically target dysregulated pathways in pathologies ranging from autoimmune and neurogenerative disease to cancer.