Stroke is currently the third leading cause of disability-adjusted life-years and mortality worldwide. As the risk of stroke increases sharply with age, incidence, and prevalence are expected to rise even further because of an aging population. This disease affects about 3.5 million people in the EU, with 700 000 new cases yearly. More than half of the patients suffer significant residual impairments, causing huge economic and societal burdens. Acute clinical intervention, typically involving surgical removal or dissolution of the clot through the administration of tissue plasminogen activator (tPA), aims to restore blood flow to the affected brain areas and is only possible within a very short time window after stroke onset. Stem cell therapy using human induced pluripotent stem (iPS) cell-derived neural precursors is a promising future therapy for stroke patients. Two main mechanisms have been proposed to give rise to improved functional recovery in animal models of stroke after the transplantation of these cells. First, the ”bystander” effect, which could modulate the inflammatory environment by releasing different factors from grafted cells, resulting in moderate improvements in the outcome of the insult. Second, the neuronal replacement and functional integration of grafted cells into the impaired brain circuitry. This will ultimately result in optimum long-term structural and functional repair. Our data show that human skin-derived cortical progenitors can be reprogrammed to differentiate into cortical projection neurons and functionally integrate (forming afferent and efferent synaptic connections) not only into stroke-damaged rat cortical networks but also into organotypic cultures of the adult human cortex. The grafted cortical neurons respond to sensory stimulation in live animals and, importantly, also affect spontaneous behavior when inhibited by optogenetic stimulation. Stroke results in the loss of oligodendrocytes and axonal demyelination, contributing to functional impairment. Additionally, for grafted neurons to become functional, their axons must be myelinated. Our data show that human iPS cell-derived cells can also be reprogrammed to differentiate into functional, bona fide oligodendrocytes. The generated cells exhibit the structural, molecular, and functional characteristics of mature human oligodendrocytes. They can wrap both grafted human cell- and host-derived axons from cortical neurons in different set-ups, after xenotransplantation into rat stroke-injured somatosensory cortex and the human adult cortical organotypic system. Our findings raise the possibility that injured neural circuitry might be restored by stem cell transplantation also in humans with stroke, which would have major clinical implications.