The dorsolateral prefrontal cortex (dlPFC) is increasingly targeted by various noninvasive transcranial magnetic stimulation or transcranial current stimulation protocols in a range of neuropsychiatric and other brain disorders. The rationale for this therapeutic modulation remains elusive. A model is proposed, and up-to-date evidence is discussed, suggesting that the dlPFC is a high-level cortical centre where uncertainty management, movement facilitation, and cardiovascular control processes are intertwined and integrated to deliver optimal behavioural responses in particular environmental or emotional contexts. A summary of the state-of-the-art in the field is provided to accelerate the development of emerging neuromodulation technologies for brain stimulation and recording for patients with mood, sleep, and cognitive disorders in our ageing population.