The activity of the renal Na‐Cl cotransporter (NCC) is regulated by WNKs. Because in Xenopus laevis oocytes the NCC activity is reduced by WNK4, but is increased by WNK3, sequences within WNKs should endow them with these properties. To gain insight into WNKs structure function relationship, we constructed chimeras between WNK3 and WNK4 by swapping the amino or carboxyl terminus domains, which flank the central kinase domain, between WNK3 and WNK4. Then, effect of chimeras upon NCC activity was analyzed by assessing thiazide‐sensitive 22Na+ uptake in oocytes injected with NCC cRNA alone or together wild type WNKs or chimeras cRNA. Our results show that NCC activity was increased by chimeras containing the amino terminal domain of WNK3 and decreased by chimeras containing the amino terminal domain of WNK4. Elimination of catalytic activity in chimeras prevented their effect upon NCC. Thus, the effect of WNK3 and WNK4 upon NCC follows the amino terminal domain. We conclude that sequences within amino terminal domain endow WNK3 and WNK4 with their activating or inhibiting properties upon NCC.