Production and excretion of acids are balanced to maintain systemic acid-base homeostasis. During metabolic acidosis (MA) excess acid accumulates and is removed from the body, a process achieved, at least in part, by increasing renal acid excretion. This acid-secretory process requires the concerted regulation of metabolic and transport pathways, which are only partially understood. Chronic MA causes also morphological remodeling of the kidney. Therefore, we characterized transcriptional changes in mammalian kidney during MA to gain insights into adaptive pathways. Total kidney RNA from control and 2- and 7-days NH(4)Cl treated mice was subjected to microarray gene profiling. We identified 4,075 transcripts significantly (P < 0.05) regulated after 2 and/or 7 days of treatment. Microarray results were confirmed by qRT-PCR. Analysis of candidate genes revealed that a large group of regulated transcripts was represented by different solute carrier transporters, genes involved in cell growth, proliferation, apoptosis, water homeostasis, and ammoniagenesis. Pathway analysis revealed that oxidative phosphorylation was the most affected pathway. Interestingly, the majority of acutely regulated genes after 2 days, returned to normal values after 7 days suggesting that adaptation had occurred. Besides these temporal changes, we detected also differential regulation of selected genes (SNAT3, PEPCK, PDG) between early and late proximal tubule. In conclusion, the mammalian kidney responds to MA by temporally and spatially altering the expression of a large number of genes. Our analysis suggests that many of these genes may participate in various processes leading to adaptation and restoration of normal systemic acid-base and electrolyte homeostasis.