In jaundice, tissues are yellow in color because of an excessive deposition of bilirubin secondary to hyperbilirubinemia. Bilirubin is the physiological end-product of heme metabolism. Jaundice is one of the main symptoms of hepatobiliary disease. Besides that, it might occur in the setting of cardiac, hematologic or pancreatic disorders. The onset of jaundice varies from acute with severe impairment of general condition to chronic and not being noticed by the patient at all. In the first part of this review, the physiological and pathophysiological molecular mechanisms of heme and bile metabolism are described in detail on a scientific basis. The knowledge of the main principles of heme degradation, canalicular bile secretion and enterohepatic cycling of bile salts helps to understand, why clinicians differentiate between prehepatic (hemolytic), hepatocellular and obstructive jaundice. A detailed patient's history and a careful physical examination are essential for the clinical differential diagnosis of jaundice. In combination with routinely obtained lab results, it is often possible to find the right diagnosis already at the bedside. To demonstrate this, the second part of this review sets the focus on the analysis of three case reports from the clinical point of view. The differential diagnosis of jaundice is summarized in a table.