The WNK family of protein kinases comprise 4 members (WNK1, WNK2, WNK3 and WNK4) and were originally identified as serine-threonine protein kinases that lack a conserved Lys residue normally found in subdomain II of the catalytic domain. Subsequent studies, identified mutations in the genes encoding WNK1 and WNK4, in families with an inherited hypertension and hyperkalemia (elevated plasma K⁺) disorder, called pseudohypoaldosteronism type II (PHAII, also known as Gordon's syndrome). WNK isoforms are large protein kinases (WNK1-2382 residues, WNK4-1243 residues), in which the catalytic domain is located at the N-terminus (residues 221 to 479 for WNK1 and 174 to 432 for WNK4). Apart from two putative coiled-coil domains, the remainder of the WNK polypeptides possess no obvious structural features. Mutations in the WNK1 gene found in PHAII subjects, are deletions in intron-1, which reportedly elevate the expression of the WNK1 protein, indicating that hypertension could result from increased expression of WNK1. Consistent with this notion, mice lacking one allele of WNK1, had lower blood pressure. The WNK1 knockout is an embryonic lethal, indicating that WNK1 is also required for normal development. Thus far, the mutations in the WNK4 gene found in PHAII subjects, lie distal to both of the putative coiled-coil domains. Little is known about the molecular mechanism by which WNK isoforms regulate cellular processes. In my talk I will present our recent results that indicate that the WNK protein kinases are activated by osmotic stress an event that is triggered by phosphorylation of Ser382 on the T-loop residue of the catalytic domain. I will present data to show that the WNK1 kinases phosphorylate and activate protein kinases of the STE20 family, termed STE20/SPS1-related Proline-Alanine-rich Kinase (SPAK) and the Oxidative Stress Response kinase-1 (OSR1) and that these kinases may regulate the activity of ion transporters such as NKCC1 and NCC. I will discuss the possibility that mutations in WNK1 and WNK4 genes in humans disrupt this pathway, thereby affecting ion transporter activity in organs such as the kidney, which could account for the development of hypertension in subjects with these mutations.