Cholestasis is a pathological condition characterized by impaired bile formation, secretion, or flow, commonly associated with various liver and systemic diseases. Clinically, it presents with an abnormal liver enzyme profile, including elevated bilirubin, alkaline phosphatase, and gamma-glutamyl transferase, with or without increased transaminases. In severe cases, patients may develop jaundice, pruritus, acholic stools, and choluria. The histopathologic features of cholestasis vary widely and include hepatocellular or canalicular cholestasis, bile ductular reaction, ductopenia, copper accumulation, and fibrosis. These changes manifest in distinct patterns—bland lobular cholestasis, obstructive cholestasis, duct injury with portal inflammation, and ductopenia—each with its own set of etiologic differentials. Given the overlap in histologic findings, accurate diagnosis requires a structured clinicopathologic approach that integrates key microscopic features with clinical, serological, and radiological data. This chapter examines common cholestatic liver diseases and their diagnostic challenges, emphasizing histopathologic characteristics and clinical correlations. To illustrate real-world complexities, this chapter concludes with four case presentations highlighting frequently encountered diagnostic dilemmas in cholestatic liver disease.