Knowledge about disease modifying antirheumatic drug (DMARD) mechanism(s) of action, kinetics and toxicities can be used to help develop rational DMARD combinations. While limited by the present lack of knowledge in these areas, the present DMARD characteristics will be used to develop rational DMARD combinations. Combinations of methotrexate (MTX) plus azathioprine, and MTX plus gold might be expected to be poor DMARD combinations, a prediction borne out by experimental studies. MTX plus cyclosporine, on the other hand, should be an effective combination, again demonstrated by a recently published clinical study. Also, hydroxychloroquine plus MTX should be a good combination, and an observational study seems to support this. However, not all predictions are accurate (probably due to inadequate data about mechanisms, kinetics, and toxicities). For example, hydroxychloroquine plus D-penicillamine had a negative interaction when tested, a result not predicted by the suggested approach. In addition, predictions are inevitably oversimplified so that what appears to be a negative interaction between MTX and sulfasalazine is not actually one when the details of the potential negative interaction between these 2 drugs are examined. Ultimately, use of a construct such as the one suggested should improve the chances of success and decrease the costs of testing DMARD drug concentrations.