Increased understanding of the mechanisms responsible for nanotoxicity and the availability of good predictive models are making possible a “safety-by-design” (SbD) paradigm for nanomaterial development for medical and other diverse commercial applications. This chapter outlines some of the main issues that SbD processes face and how the difficulties can be overcome using a combination of experiments on the effects of nanomaterials on biological systems and advanced material modeling methods. One of the main limitations to the derivation of widely applicable, useful models of the adverse effects of nanoparticles is the dearth of relevant biological data. The need for rigor in the way data on nanoparticles and their biological effects are collected and stored is discussed by Marchese Robinson and coworkers. The application of nanotechnology to medicine has been accelerating faster than research into identifying adverse biological effects of nanomaterials. The opportunities and challenges associated with the development of multifunctional nanomaterials and nanotheranostics have been reviewed by A. Radomska et al.