TP53 gene encodes a protein called tumor protein p53 which acts as a critical tumor suppressor. Mutations of p53 are highly found in human cancers, and most of the hotspot mutations of p53 will cause its loss of functions (LOF). LOF of p53 mutants are correlated with high-level of drug resistance. In addition, some of the hotspot p53 mutants also acquire some oncogenic functions called as gain of functions (GOF). GOF of mutants p53 are highly associated with late-stage malignance, greater chemoresistance and multiple drug resistance. In this special issue is focused on targeting of LOF or GOF p53 mutants for developing cancer therapies.