In the last few years management of rheumatoid arthritis (RA) has changed substantially due to the availability of new drugs and newer therapeutical strategies. Controlled randomised clinical trials (RCT) have allowed us to analyse the efficacy and safety of all these innovative approaches. Unfortunately, these RCTs are not free from criticisms and their rigid inclusion and exclusion criteria may increase the differences between the ideal patients enrolled and the majority of patients seen in standard clinical care. This review focuses on actual clinical practice, with particular attention on patient comorbidities and all the conditions which have been designated as exclusion criteria in the most important registration RCTs. We will attempt to provide an overview of the most widely used strategies in RA therapy.