RA is a syndrome consisting of different pathogenetic subsets in which distinct molecular mechanisms may drive common final pathways. Recent work has provided proof of principle that biomarkers may be identified predictive of the response to targeted therapy. Based on new insights, an initial treatment algorithm is presented that may be used to guide treatment decisions in patients who have failed one TNF inhibitor. Key questions in this algorithm relate to the question whether the patient is a primary vs a secondary non-responder to TNF blockade and whether the patient is RF and/or anti-citrullinated peptide antibody positive. This preliminary algorithm may contribute to more cost-effective treatment of RA, and provides the basis for more extensive algorithms when additional data become available.