Background: Nanosafety aims for a solution through the safer design (and re-design) of nanostructured materials, optimizing both performance and safety, by resolving which structural features lead to the desired properties and modifying them to avoid their detrimental effects without losing their desired nanoscale properties in the process. Starting with known toxic NPs, the final aim should be the re-design of such detrimental specific NP characteristics and to redefine the way they should be manipulated from the beginning to the end of their life cycle. Methods: The researchers reviewed literature in the area of novel nanosafety strategies addressing the “safe-by-design” paradigm. Results: The potential hazards of engineered NPs are not only determined by the physicochemical properties of the engineered NPs per se but also on the interactions of these NPs with immediate surrounding environments. The aim of promoting the timely and safe development of NPs cannot be achieved via traditional studies as they address one material at one time. The development of a safer design strategy of engineered NPs requires an understanding of both intrinsic (synthetic) properties together with their extrinsic responses to external stimuli. Conclusions: We have summarized recent developments of novel nanosafety strategies addressing the “safe-by-design” paradigm for optimizing both performance and safety, allowing the comparison of results of different studies and ultimately providing guidelines for the re-design of safer NPs. The resulting discussion is intended to provide guidelines for synthetic nanochemists on how to design NPs to be safe during their full life cycle while maintaining their parental desired properties.