The use of Immersive Virtual Reality Environments (iVREs) for training and rehabilitation purposes is growing in popularity. An emerging topic in iVRE program development, particularly programs aimed at cognition enhancement, is implementing two-way interactions between the user’s cognitive state and the iVRE to achieve maximal effects. This process incurs several outstanding challenges. For example, although recent advances in electroencephalography (EEG) have revealed a number of neural correlates/signatures for a variety of operationally-relevant cognitive states (e.g., attentiveness, fatigue), most if not all of these neuromarkers have not been validated in iVREs. The current paper addresses this gap by describing efforts to achieve high quality EEG signals in an iVRE with millisecond-time synchronization between the two systems. To achieve these goals, we evaluated several mobile EEG systems, incorporated off-the-shelf hardware, and developed custom software to effectively implement the EEG devices into the Physical and Cognitive Operational Research Environment (PhyCORE), an iVRE located at the Naval Health Research Center in San Diego, California. As a result, the PhyCORE can now provide cognitive information about human subjects through on-line monitoring of brain activity patterns. Equipped with this capability, the PhyCORE is ready for further development of individualized training and rehabilitation programs based on the subjects’ cognitive states as assessed in real-time and in a real-life environment. The technical challenges and solutions described herein can be easily generalized and adapted for other iVREs, and represent a critical step toward optimization of the human-machine interaction.