CSK (C-terminal Src kinase) is a non-receptor tyrosine kinase that functions as a critical negative regulator of Src-family kinases (SFKs), including LCK, SRC, HCK, FYN, and LYN 1. CSK phosphorylates conserved tyrosine residues in the C-terminal tails of SFKs, inducing intramolecular interactions that lock these kinases in an inactive conformation 2. This mechanism suppresses signaling downstream of T-cell receptors (TCRs) and B-cell receptors (BCRs) by inhibiting positive effectors such as FYN and LCK 3. CSK is recruited to the plasma membrane through its SH2 domain binding to transmembrane adaptor proteins, particularly PAG/Cbp, which facilitates membrane localization and enhances kinase activity 4. CSK haploinsufficiency increases blood pressure through elevated active Src in vascular smooth muscle, identifying CSK as a causative gene at the 15q24 hypertension locus 5. Reduced CSK expression or activity is associated with elevated SFK signaling in human cancers, suggesting CSK loss contributes to oncogenic transformation 1. Thus, CSK functions as an essential brake on Src-family kinase signaling, with particular relevance to immune regulation and cardiovascular homeostasis.