The with-no-lysine (K) (WNK) family of protein kinases is unique in that they are characterized by a more exposed position of the catalytic lysine in the kinase domain when compared to canonical protein kinases. These kinases have been implicated in regulation of a variety of cellular processes such as salt and water homeostasis, intracellular vesicular trafficking, and neuronal excitability. Mutations in two of the four family members have been linked to Gordon’s syndrome which is a genetic hypertensive disease. Recent evidence points to a role of these proteins in several other disease systems including cancer. Newer studies suggest that these proteins are an ancient class with homologs found in unicellular organisms and plants. In this article, we review the different roles of WNK family members in mammals and plants, links with other pathways in the cell and its role in disease.