Timeline of the development of biologic combinations. This journey started with single-agent rituximab, which, when active in the relapsed setting was studied as initial treatment. Doublets of monoclonal antibodies were studied by CALGB investigators, which then were followed by their study of R² in relapsed FL and, subsequently, as initial treatment. The addition of idelalisib to R² was associated with prohibitive toxicity and, with ibrutinib, without a sufficient signal of improved efficacy to pursue further. Currently, numerous studies of doublets and triplets of targeted agents with or without an anti-CD20 are being conducted, with many more anticipated.