The introduction of TNFalpha inhibitors has radically changed the management of patients with refractory rheumatoid arthritis (RA) or spondyloarthropathy. However, among patients with RA unresponsive to methotrexate, only two-thirds respond to TNFalpha inhibitors. Fortunately, more than 5 years after infliximab was introduced on the market, preliminary evidence that emerging biological agents are effective is beginning to accumulate, generating new hope for patients who fail to respond to TNFalpha inhibitors. These novel biological therapies grew out of original pathophysiological hypotheses, a fact that vividly illustrates the importance of basic pathophysiological research for developing new medications. This review provides detailed information on three biological therapies whose efficacy in RA was demonstrated in recently published randomized placebo-controlled trials: a monoclonal antibody to the IL-6 receptor (MRA), CTLA4-Ig (abatacept), and a monoclonal B-cell-specific antibody to CD20 (rituximab). Good risk/benefit ratios seem to be achieved with MRA alone or with abatacept or rituximab combined with methotrexate. However, as yet, no radiographic data are available for these treatments. One of the challenges for the future is to identify ingenious combinations of biological therapies capable of improving the quality and duration of responses without exacerbating side effects.