The man-in-simulant test (MIST) is one of the most widely used methods for evaluating a chemical protective ensemble's (CPE's) ability to resist infiltration of hazardous gases and vapors. Unlike material-level tests that only characterize the ability to resist permeation or penetration directly through the material, MIST provides an assessment of the whole ensemble, including the materials, seams, zippers, closures, and other interfaces. Standard MIST methods for first-responder usage (approximately 30 min of exposure) described in ASTM F2588-12, Standard Test Method for Man-In-Simulant Test (MIST) for Protective Ensembles, and the National Fire Protection Association's NFPA 1994, Standard on Protective Ensembles for First Responders to CBRN Terrorism Incidents (2012 edition), were intended to be used for nonencapsulating CPE that provide moderate to lower levels of protection, which correspond to NFPA 1994 Class 2 and Class 3 ensembles. Because fully encapsulating ensembles (NFPA 1991 or Environmental Protection Agency Level A) are designed to completely separate the end user from the hazardous external environment, the amount of the chemical simulant that enters the ensemble and is adsorbed onto the passive air samplers is significantly lower than for the Class 2 or Class 3 type ensembles. The ability to detect this lower amount within the current standard conditions pushes the analytical methods and instrumentation to their operating limit. Therefore, to more accurately evaluate fully encapsulating ensembles, some alterations to the standard methods must be taken into consideration. This research discusses the potential approaches that can be taken to make MIST methods more appropriate for evaluating fully encapsulating ensembles. These approaches include increasing the challenge exposure dosage, altering the air sampler properties, or enhancing the analytical detection limits (or any combination thereof). In addition, toxicologically relevant data are used to derive and suggest a new performance requirement for the NFPA 1991 ensembles.