Acid-base homeostasis is one of the most tightly regulated systems in the body. Maintaining the acid-base balance is particularly challenging for preterm infants and growing neonates. The kidney, which represents the crucial ultimate line of defense against disturbances of acid-base balance, undergoes a complex maturation process during the transition from a fetal to an extra-uterine environment. This review article summarizes the physiology of acid-base regulation by the immature human kidney and discusses disorders of acid-base balance, such as metabolic acidosis, respiratory acidosis, metabolic alkalosis, and respiratory alkalosis. In conditions of metabolic acidosis, the serum anion gap and the urinary anion gap can be useful tools to define the nature of the acidosis. Metabolic acidosis can reflect a decrease in glomerular filtration rate, or be the consequence of selective disorders of proximal or distal tubular function. Most tubulopathies associated with metabolic acidosis observed in neonates are primary, hereditary, isolated tubulopathies. Proximal renal tubular acidosis is characterized by bicarbonate wasting, while the distal types of renal tubular acidosis are secondary to distal acidification defects. All tubulopathies are associated with hypokalemia, with the exception of type 4 hyperkalemic distal renal tubular acidosis. The transporter defects in the various acid-base tubulopathies are now well defined. Treatment of the acidosis varies according to the site and mechanism of the defect. Chronic renal tubular acidosis or alkalosis severely impair growth and calcium metabolism. Early rational therapeutic intervention can prevent some of the consequences of the disorders and improves the prognosis.