Aberrant p53 function is one of the major requirements for tumor development. Reactivation of p53 function by small molecules is a promising strategy to combat cancer due to potent tumor suppressor activities of p53. Recent developments in p53 biology reveal that manipulation of p53 function might pave way to a long cancer-free life. A number of small molecules which rescue p53 function by different mechanisms, acting upstream of p53 or targeting the p53 protein itself have been identified. Notably, these molecules trigger different biological outcomes, suggesting that it might be feasible to direct p53-mediated response in a desired way. In this review I discuss the latest developments in the search for small molecules which rescue p53 function by targeting the p53 protein.