New paradigms of disease modifying antirheumatic drug based treatment strategies for rheumatoid arthritis (RA) raise new questions of sequencing of medications and employment of combination therapy. A broader view of chronic illness indicates that nonbiologic and self-management factors influence disease course and necessitate inclusion of patient oriented outcome measures such as disability and pain. I discuss these and related issues, present a broad model of disease progression in RA, introduce the concept of the "therapeutic segment," describe the dependence of clinical results on immediately prior therapy, and suggest a new research approach into the merits of combination therapy. Effectiveness is not necessarily increased by addition of a 2nd drug, nor is toxicity necessarily increased by combination therapy.