Nanotechnology is an emerging science involving manipulation of matter at the nanometer scale. Due to concerns over nanomaterial risks, there has been a dramatic increase in focused safety research. The present review provides a summary of these published findings, identifying areas of agreement and discordance with regard to: (1) the potential for nanomaterial exposure, (2) the relative hazard nanomaterials pose to humans and the environment, and (3) the present deficits in our understanding of risk. Special attention is paid to study design and methodologies, offering valuable insight into the complexities encountered with nanomaterial safety assessment. Recent data highlight the impact of surface characteristics on nanomaterial biocompatibility and point to the inadequacy of the current size-dependent mechanistic paradigms, with nanoscale materials lacking unique or characteristic toxicity profiles. The available data support the ability of the lung, gastrointestinal tract, and skin to act as a significant barrier to the systemic exposure of many nanomaterials. Furthermore, the acute systemic toxicity of many nanomaterials appear to be low. By contrast, the potential pulmonary toxicity of certain nanomaterials, such as carbon nanotubes, is significant, requiring a better understanding of exposure to further evaluate their risk. While these findings arrive at an overall picture of material-specific rather than nanogeneralized risk, any conclusions should clearly be tempered by the fact that nanomaterial safety data are limited. Until such time as the exposures, hazards, and environmental life cycle of nanomaterials have been more clearly defined, cautious development and implementation of nanotechnology is the most prudent course.