Abstract The approval of brentuximab vedotin (BV) and the PD-1 inhibitors nivolumab and pembrolizumab has dramatically improved outcomes for patients with relapsed or refractory (R/R) classic Hodgkin lymphoma (HL). With the goal of increasing long-term disease control rates and decreasing late toxicities, these agents are currently being tested in earlier phases of treatment in combination with chemotherapy agents. In the R/R setting, our expanding understanding of HL’s various mechanisms of immune evasion and treatment resistance has spurred a growing number of rationally designed combination trials. Beyond BV and PD-1 blockade, other novel therapies have demonstrated encouraging preliminary results, including targeted agents, like the CD25 antibody-drug conjugate ADCT-301, and cellular therapies, including CD30 chimeric antigen receptor T cells and Epstein-Barr virus (EBV)-directed cytotoxic T cells. These trials, coupled with the rapid development of prognostic and predictive biomarkers, should drive additional breakthroughs that promise safer and more effective therapies for patients with HL in the future.