In honor of the recent 40th anniversary of the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines) as well as the emergence of new technologies in the life sciences, it is an opportune time to examine the current biosafety oversight framework, and discuss the future direction of biosafety oversight. In the decades since scientists gathered at Asilomar, there has been considerable evolution in molecular biology, our understanding of risk and safety, and biosafety oversight. While recombinant DNA has become ubiquitous, new emerging technologies – ranging from new genome editing tools to novel RNA applications – are presenting interesting challenges to our current biosafety framework.