In the second volume of this special issue, we focus on the activity and function of the mutant p53 proteins. The elegant work of Nakayama and Oshima (2019) uses mouse models of colorectal cancer to directly demonstrate the role that expression of the R273H protein has in promoting invasion. Using both animal studies and organotypic cultures, they are able to demonstrate that the gain-of-function (GOF) is driven by high-level nuclear expression of the protein and that this high-level expression requires escaping from Mdm2-dependent degradation and environmental influence that are especially seen at the invading front of the tumor. Their studies show that wild-type p53 can inhibit the GOF of the mutant protein providing clear support for the need for loss of the wild-type allele as the tumor progresses. This elegant in vivo work shows that the dominant-negative function of mutant p53 proteins has limited penetrance and helps to clarify this controversial area.