In the last two decades the field of tumor suppressor genes (TSG) has developed from a novel epidemiology-based concept into one of the pillars of cancer research. New TSG are being discovered and although at a painstakingly slower pace, their functions are also being unravelled. These breakthroughs have not only brought about immediate benefits to clinical medicine such as genetic predictive testing for familial cancer syndromes, but have also introduced new strategies against cancer including early intervention, prevention and promising anti-cancer drugs. Despite that, we are still far from fully understanding the functional complexity of TSG with each discovery leading to even more queries. New developments that challenge the paradigm of TSG have also surfaced warranting verification and there is still a lack of consensual criteria and systematic cataloging for TSG. With the advent of high throughput sequencing and powerful bio-informatics, it is expected that the field of TSG will be expanding at an even faster pace. This review is to give a summary of the history, new concepts and recent advancements in the field of TSG in the hope that some of these concepts and works can be evaluated, expanded or even challenged.