Research and business investment in emerging nanotechnologies is leading to a diverse range of new substances and products. As workers are faced with handling new materials, often with novel properties, the robustness of current workplace health and safety regulatory frameworks is being brought into question. Here, 12 characteristics of the U.S. occupational safety regulatory framework identified by Choi and Ramachandran are considered in the context of emerging nanotechnologies. The assessment suggests that, as the number of new materials entering the workplace continues to increase, OSHA will need to develop flexible approaches to identifying and reducing potential risks. Relying on conventional approaches in the face of unconventional challenges will increase the probability of otherwise avoidable heath impacts. If the potential for engineered nanomaterials to cause harm is to be understood and managed, the agency will need to look at new approaches to generating, sharing, and using information.