This review supports the idea that the mapping of cellular and system-level networks to both on (excitatory) and off (inhibitory) circuit phenotypes specific to treatment-resistant disease may be a productive strategy in expanding future research toward customized neural circuit-specific pharmacotherapeutics and directed neuromodulation treatments in schizophrenia. Targeted therapeutics that can improve particular areas of regional functional dysconnectivity that are found to be substantially affected in TRS is an intriguing approach to precision medicine in schizophrenia.