Primary sclerosing cholangitis (PSC) is a progressive idiopathic fibrosing liver disease which leads to multiple biliary complications often best managed with endoscopic retrograde cholangiopancreatography (ERCP). PSC biliary complications include dominant biliary strictures, bile duct stones, cholangitis, and cholangiocarcinoma (CCA). Balloon dilation is the preferred treatment for management of dominant strictures as biliary stenting has been associated with higher rates of adverse events (AEs). Biliary stenting is reserved for patients with benign refractory strictures or CCA. Multiple tools are available for biliary tissue acquisition including endoscopic ultrasound, biliary brushing for cytology, and fluorescent in situ hybridization (FISH), cholangioscopy, and transpapillary biopsy. The combination of FISH and cytology improve the sensitivity of biliary brush sampling for malignancy. Cholangioscopy improves tissue acquisition in equivocal situations. Obtaining at least 3 biopsy samples yield better results with transpapillary biopsy. Post-ERCP AEs are similar to the general population. However, cholangitis can result from inadvertent contrast introduction into undrainable segments and thus PSC patients should receive peri-procedural antibiotics. ERCP-directed interventions are effective for therapy of PSC biliary complications. Tissue sampling for CCA is challenging but multiple tools are available and combinations of these techniques are often required to obtain a tissue diagnosis.