Cardiac surgery patients may develop significant acid-base disturbances due to cardiac pathology, comorbidities, type and duration of surgery, and cardiopulmonary by-pass (CPB). The evaluation of acid-base status through arterial blood gas (ABG) analysis is essential for adequate perioperative treatment and hemodynamic optimization. Modern approaches, including the calculation of anion gap, standard base excess, and strong ion difference, improve the diagnostic accuracy beyond the traditional Henderson-Hasselbalch method. Recent evidence emphasizes the importance of balanced, plasma-adapted fluids and a tailored approach to bicarbonate administration in severe metabolic acidosis. Furthermore, persistent acid-base imbalances in the post-operative period are associated with increased morbidity and mortality. This chapter provides a comprehensive overview of acid-base physiology, its pathophysiology in cardiac surgery, and an updated interpretation framework of ABG analysis for clinical practice.