Point mutations in WNK4, a serine threonine kinase that is expressed in the distal nephron of the kidney, are linked to familial hyperkalemic hypertension (FHH). The imbalanced electrolytes homeostasis in FHH has led to studies toward an understanding of WNK4-mediated regulation on ion transport proteins in the kidney. A growing number of ion transport proteins for Na⁺, K⁺, Ca²⁺, and Cl^-, including ion channels and transporters in the transcellular pathway and claudins in the paracellular pathway are shown to be regulated by WNK4 from studies using models ranging from Xenopus laevis oocytes to transgenic and knockin mice. WNK4 regulates these transport proteins in different directions and by different cellular mechanisms. The common theme of WNK4-mediated regulation is to alter the abundance of ion transport proteins at the plasma membrane, with the exception of claudins which is phosphorylated in the presence of WNK4. The regulation of WNK4 can be blocked by the full-length WNK1, whose action is in turn antagonized by a kidney-specific WNK1 variant lacking the kinase domain. In addition, WNK4 also activates stress-related serine-threonine kinases to regulate members of the SLC12 family members of cation-chloride cotransporters. In many cases, the FHH-causing mutants of WNK4 exhibit differences to the wild-type WNK4 in regulating ion transport proteins. These regulations well explain the clinical features of FHH and provide insights into the multilayered regulation of ion transport processes in the distal nephron.