Twenty years ago, cognitive impairments were recognized as an unmet treatment need in schizophrenia. Basic science discoveries in neuroplasticity had led to cognitive training approaches for dyslexia. We wondered whether a similar approach could target working memory deficits in schizophrenia by harnessing plasticity in the auditory cortex. Our per protocol experimental therapeutics studies tested the hypothesis that sharpening auditory cortical representations would result in better verbal learning and memory. We also later studied the effects of intensive training of basic social cognitive operations. Our training protocols were deliberately focused, effortful and intensive, since participants were often up against decades of cortical dysplasticity. In studies in different stages of illness, we demonstrated that neuroscience-informed cognitive training was associated with: (1) proximal psychophysical as well as distal cognitive improvements; (2) increases in serum BDNF levels; (3) negative effects of serum anticholinergic burden; (4) electrophysiologic responses and brain activation patterns consistent with restorative neuroplastic changes in cortex; (5) positive cortical and thalamic volumetric changes suggestive of neuroprotection; (6) better 6-month clinical functioning in those with a positive initial response. Taken together, this work indicates how much the field of psychiatry could benefit from a deep understanding of the basic science of cortical neuroplasticity processes and of how they can be deliberately and efficiently harnessed for therapeutic purposes.