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It has proven difficult to establish robust evidence for significant clinical benefits of medical treatment in primary sclerosing cholangitis (PSC). For ursodeoxycholic acid, clinical practice guidelines only offer vague recommendations, leading to a situation of variable prescription rates depending on local reimbursement policies and physician preference. The difficulty in drug development in PSC is partly related to a poor understanding of critical disease processes with failure to identify relevant mechanisms of action of putative drugs. The variable disease course, both intra-individually and between individuals, and the lack of robust definitions of what success looks like for clinical trials in PSC have also contributed to the negative outcomes of trials performed. In this review article, we will discuss these uncertainties and challenges, building on key previous and ongoing clinical trials. Despite the lack of consensus for ideal phase II and phase III study designs, several trials for diverse compounds are currently ongoing, indicating a shift from therapeutic nihilism toward hope for people with PSC. While waiting for robust efficacy data for drugs currently being tested, the current lack of effective interventions should not motivate the prescription of compounds to people with PSC based on low-quality evidence., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)