As a discipline of its own, bio risk management has evolved rapidly over the past 10  years. Implementation of a systematic bio risk management approach remains uneven globally, and new, poorly understood bio risks continue to emerge that challenge traditional approaches to biosafety and biosecurity.* In this chapter, we discuss some of the challenges facing the discipline of bio risk management, and consider approaches to addressing them. Many of these challenges relate to the inherently diverse and variable nature of biological risks, the different existing systems to assess and address these risks, variability in risk tolerance at the local and international levels, and the availability of data and determination of criteria to support the selection and application of these systems within organizations that are operating in different geographical, social, and legal environments. This chapter will consider how the regional differences in assessing and controlling bio risks can be understood in a way that will eventually permit contextual comparison of bio risk management cornerstones based on the assessment, mitigation, and performance model.