<p>Disorders of consciousness (DoC) following severe brain injury represent a formidable clinical challenge, with limited therapeutic options for patients in prolonged unresponsive or minimally conscious states. Deep brain stimulation (DBS) of the central thalamus has re-emerged as a pivotal strategy to restore arousal and functional communication. In this review, we integrate systems neuroscience with clinical evidence to delineate the transition of DBS from an experimental intervention toward circuit-guided precision medicine. We first articulate the mesocircuit hypothesis, positing that DBS acts not by local excitation alone, but by reversing a circuit-level collapse driven by striatal deafferentation and excessive pallidal inhibition. Synthesizing recent clinical data, we highlight an emerging reinterpretation of targeting, in which efficacy may depend less on named anatomical nuclei than on the recruitment of preserved arousal conduits and fronto-striatal projections—a hypothesis supported by connectomic analyses but awaiting direct causal validation. Furthermore, we discuss the redefinition of patient selection through Cognitive Motor Dissociation (CMD) and the evolution of stimulation paradigms toward biomimetic, adaptive control policies (e.g., 40–60 Hz state-dependent modulation). Finally, we address the ethical framework of “consent under uncertainty” essential for responsible translation. We conclude that while heterogeneity remains a hurdle, combining connectome-based targeting with sensing-enabled technologies offers a viable roadmap to validate DBS as a standard of care for carefully selected patients.</p>