The advent of biologic therapies for the treatment of rheumatoid arthritis (RA) has radically changed this therapeutic area. The currently available biologic agents have been studied extensively as part of their development and also during their subsequent years of use in clinical practice; as a result, the knowledge base regarding these therapeutics is very large. Nonetheless, a number of important questions remain and some key issues are still incompletely understood. In this Review, I discuss a number of these unresolved issues, including: the correct placement of biologic therapies in the long-term evolution of the RA disease process, and the expectations associated with such use; comparisons of therapeutic strategies that include conventional as well as biologic agents; optimal dosing of biologic agents; the elusive goal of personalized therapy; and an appraisal of the real impact of biologic therapy on patients' lives. It is concluded that, despite these unresolved issues, important progress has been made and many additional advances in our understanding can be expected during the coming years.