Nanotechnology-enabled systems offer much promise for solving difficult environmental problems ranging from water purification to waste remediation. These solutions must not only be cost-effective and sustainable, but they must also be safe for people and the environment. Our emerging understanding of the interface between nanomaterials and biological systems gives us the critical ability to approach the latter issue early in the development of nanotechnology. This talk will discuss in some detail how the chemical and physical properties of engineered nanomaterials impact their biological effects in model systems. Three case studies, ranging from fullerenes to metal oxides, illustrate the vast diversity of nanomaterial features and biological response. The composition of a nanomaterial is the primary factor in describing acute biological effects, and among the different examples nanoparticle charge and surface coating can be of equal importance. Interestingly, the size of the inorganic material itself – such an important feature for applications development – in these three examples is secondary in defining the materials’ acute biological effect. In all cases, the biological and environmental compartments experienced by nanomaterials lead to substantial modification of their hydrodynamic size and charge. The bio-modified material that results is the central element to understand and characterize in order to detect the underlying correlations between the inorganic nanomaterial phase, composition and size with biological outcomes. These correlations form the basis for guidelines that permit researchers creating new nanoparticles to focus their energy on materials that are ‘safe by design’.