Mice lacking the STE20/SPS1‐related proline‐alanine‐rich protein kinase (SPAK−/−) manifest a salt‐wasting nephropathy similar to Gitelman's syndrome but distinguishable from Bartter's syndrome in that the animals maintain furosemide sensitivity (Yang et al, JASN. Nov 2010). Consistent with these observations, NCC expression was dramatically reduced in SPAK−/−. NCC and SPAK are co‐expressed in the aldosterone sensitive distal nephron where NaCl reabsorption is tightly regulated to facilitate proper vascular volume. We hypothesized that the physiological regulation of NCC by NaCl availability/vascular volume is lost in SPAK−/−. Wildtype mice (WT) and littermate SPAK−/− were fed a Na deficient, control, or high Na diet for 10 days. Analysis of urine samples revealed that SPAK−/− have an elevated rate of naturiuresis but maintain a normal kaluretic response. Western blot analysis showed that total NCC abundance was reduced in SPAK−/− compared to WT under all dietary conditions, and NCC phosphorylation (@T58) was nearly absent in SPAK−/−. These results were confirmed by immunohistological studies, which also showed NKCC2 phosphorylation and expression are equal to or greater in SPAK−/− than in WT. These results suggest NCC, not NKCC2, is the primary target of SPAK‐dependent regulation, and that SPAK is necessary to maintain the physiological regulation of NCC during changes in dietary NaCl availability.