Rheumatoid arthritis and ankylosing spondylitis are common and severe chronic inflammatory skeletal diseases. Recognizing the differences rather than emphasizing similarities is important for a better understanding of the disease processes, the identification of specific therapeutic targets and in the long-term better treatment options for the individual patients. We discuss a number of pathophysiological differences between rheumatoid arthritis and ankylosing spondylitis by looking at the anatomical characteristics, differences and similarities in the autoimmune and autoinflammatory reactions, association with other immune mediated inflammatory diseases, structural outcome, and their potential significance for further therapeutic developments. Further research into the differences between these diseases should focus on the specific nature of the immune/inflammatory components, the role of resident cells in the joint and joint-associated tissues, the types and mechanisms of tissue remodeling and the characteristics of the articular cartilage. Better insights into their individual characteristics may lead to better therapeutic strategies, specific targets and useful biomarkers.