Systems neuroscience employs a network and topological perspective to elucidate the paradigm “brain.” The attribution of perception, cognition, consciousness, and behavior to findings obtained from multimodal physiological research, neuroimaging, and clinical neuromonitoring represents a significant aspect of the field within translational neuroscience. From a clinical perspective, there is great hope that advances in the treatment of severe neurofunctional disorders will be driven by the examination of the “big data” now available. Examples of clinical applications include the study of severe brain injury, coma, and (disorders of) consciousness. This brief introduction will delineate the fundamental principles of systems neuroscience, computational models, bioinformatics, and artificial intelligence as they pertain to the clinical use and investigation of ketamine. The meaning of this research for innovative therapeutic approaches and the importance of “real-world brain and body biology” within the strengths and weaknesses of translational systems neuroscience will be outlined.