Rheumatoid arthritis in the 80s was a crippling and life shortening disease, as bad as cancer. But understanding of the rate limiting steps converting autoimmunity to inflammation with joint destruction and major vascular infectious and respiratory complications has changed all that. There are no more rheumatoid arthritis inpatients, wheelchairs, little joint surgery. This therapeutic advance was started by use of methotrexate a drug of unknown mechanism but amplified by anti-TNF therapy based on work with human disease tissue. The mechanisms were unravelled by focusing on a new hypothesis emphasising the role of cytokines in autoimmunity. This seminal work documenting the pivotal role of TNF and the use of methotrexate as a cotherapeutic will be reviewed and is the current state of the art. A dilemma is that there has been no improvement for years. Other therapeutics emerged that are similarly effective, e.g. tocilizumab, developed by Prof Kishimoto, and abatecept. The case will be presented that it is possible to get close to a cure safely by judicious use of combination therapy adding another therapeutic to this regime, provided it does not interfere with host defence against infection. This my favourite target for another added on therapeutic would be those involved in the stroma, in the fibroblast like synoviocytes, in particular MMP14 which Prof Yoshi Itoh (Kennedy) has shown synergizes with anti-TNF in mouse models. New technologies, properly applied analysis of human disease tissue, immunology and molecular biology have revolutionized therapeutics, and the commercial success of anti-TNF therapy (now the world’s best-selling drug class) triggered the more widespread use of monoclonal antibodies. The quality of life and its duration have been transformed in RA and many other chronic inflammatory diseases, but the next step, trying to get to a cure still awaits us.