The global market for nanomaterial-based products is forecasted to reach 100 billion dollars per annum for 2011-2015. Extensive manufacturing and the use of engineered nanomaterials have raised concerns regarding their impact on biological response in living organisms and the environment at large. The fundamental properties of nanomaterials exhibit a complex dependence upon several factors such as their morphology, size, defects, and chemical stability. Therefore, it is exceedingly difficult to correlate their biological response with their intricate physicochemical properties. For example, varying toxic response may ensue due to different methods of nanomaterial preparation, dissimilar impurities, and defects. In this review, we surveyed the existing literature on the dependence of cytotoxicity on physicochemical properties. We found that ENM size, shape, defect density, physicochemical stability, and surface modification to be the main causes that elicit altered physiological response or cytotoxicity.