In this review, we examine TRS from a circuit-based perspective. We start by highlighting the historical development of connectome science in schizophrenia, identifying those early pioneers in psychiatry who originally recognized the disease as an illness of widespread disconnectivity and their valuable contribution to the evolution of network science today. We then examine neuroimaging studies that support both systemic and circuit-level brain dysconnectivity specific to treatment resistance and attempt to explain underlying circuit biology and brain topology that may be unique to this most severe form of the illness. Within a connectome context, attempts to map on-off circuit connectivity synonymous with excitatory and inhibitory neuronal pathways are discussed. Functional correlates of dysconnectivity in schizophrenia are also considered with a focus on cortical network oscillations, giving particular emphasis to the role of gamma band oscillations (GBOs) and their ability to integrate information across large populations of neurons in the illness. Mechanistic models describing underlying neural circuitry and the complex relationship involved in the synchronized firing between excitatory pyramidal cells and inhibitory gamma-aminobutyric acid (GABA)-ergic interneurons are also reviewed to help visualize and understand the inter-relationship between neuronal ensembles within the brain and the complex mechanisms behind their dysfunctional communication in schizophrenia. Finally, we deconstruct how augmenting pharmacological treatments, such as glutamate N-methyl-D-aspartate (NMDA) receptor and GABA interneuron modulators as well as nitric oxide (NO)-based treatments may be applied within a circuit context to improve circuit integration and treatment response in TRS. Updates on neurosurgical and neuromodulation targets under investigation in TRS are also included and provide an overview of beneficial circuit-based targets that may improve treatment resistant symptoms in those patients that remain refractory to pharmacological approaches.