Molecular grafting is a strategy for the engineering of molecular scaffolds into new functional agents, such as next-generation therapeutics. Despite its wide use, studies so far have focused almost exclusively on demonstrating its utility rather than understanding the factors that lead to either poor or successful grafting outcomes. Here, we examine protein evolution and identify parallels between the natural process of protein functional diversification and the artificial process of molecular grafting. We discuss features of natural proteins that are correlated to innovability-the capacity to acquire new functions-and describe their implications to molecular grafting scaffolds. Disulfide-rich peptides are used as exemplars because they are particularly promising scaffolds onto which new functions can be grafted. This article provides a perspective on why some scaffolds are more suitable for grafting than others, identifying opportunities on how molecular grafting might be improved.