Disorders of acid-base balance are commonly encountered in clinical practice and can have a substantial impact on the prognosis of the patient. Moreover, identification of a particular acid-base disturbance can provide a clue to an underlying disorder. Proper evaluation and treatment of acid-base disorders requires a systematic and analytic approach including: (1) assess the accuracy of the acid-base values using the Henderson equation or Henderson-Hasselbalch equation, (2) obtain a complete history and physical examination, (3) calculate the serum anion gap, (4) identify the primary acid-base disturbance and determine whether a simple or mixed disturbance is present, (5) examine serum electrolytes and additional laboratory data, and (6) measure urine pH and urine electrolytes and calculate the urine anion and osmolal gaps. Strict adherence to these principles will enable the clinician to diagnose the acid-base disturbance in the majority of cases. To illustrate these principles, 5 cases of patients with acid-base disturbances are analyzed.