Primary biliary cholangitis (PBC) is an autoimmune inflammatory liver disease of the interlobular bile ducts that can lead to cirrhosis and liver failure. Until recently, the only effective treatment was ursodeoxycholic acid (UDCA). However, up to 40% of PBC patients have an inadequate response to UDCA and may continue to have disease progression. Several models have been developed, including the UK-PBC and GLOBE scores, to assist in identifying patients who may benefit from second-line therapies, such as the farnesoid X receptor (FXR) agonist obeticholic acid (OCA). The addition of OCA can significantly improve serum alkaline phosphatase and total bilirubin, which are strong surrogate markers of clinical outcomes in PBC. Other alternatives, including the peroxisome proliferator-activated receptor (PPAR)-α agonists fenofibrate and bezafibrate, may also improve liver biochemistries in PBC patients with an inadequate response to UDCA, but further study is needed to demonstrate their safety and long-term efficacy. Other novel agents, including those targeting the FXR pathway and PPAR-δ agonists, have shown promising results and may alter the therapeutic landscape of PBC in the near future. For now, OCA remains the only approved second-line agent for PBC patients with an inadequate response to UDCA while results of long-term studies of its safety and clinical benefit are awaited.