Abstract The treatment of Hodgkin lymphoma (HL) relies on multimodality treatment with standard chemotherapy, radiation therapy, and autologous or allogeneic stem cell transplantation in cases of relapsed disease. Genomic advances in HL provided insights into deregulation of key nodal signaling pathways, including the PI3K, NF-κB, and JAK/STAT pathways, which are amenable to small-molecule targeting. Understanding how HL cells interact and depend on their microenvironment for survival signals and immune protection may uncover other such pathways. Small-molecule targeting has the potential to dramatically improve treatment outcomes, especially in patients with highly refractory disease and those with poor tolerance to existing chemotherapies. As novel therapies continue to be developed for HL, the challenge will be to address the needs of high-risk groups, reduce long-term therapy-related morbidity, position current established treatments with novel therapies, and concurrently develop biomarkers to aid in patient selection. Brentuximab vedotin, which was approved in 2011, is already shifting the treatment paradigm of HL. Undoubtedly, other novel therapeutics in the pipeline will affect positively the landscape of treatment in HL.