Abstract: Transplantation of neuronal precursors derived from human pluripotent stem cells is a promising therapy for the treatment of neurological disorders associated with neuronal loss, such us neurodegenerative diseases, brain trauma and stroke. The functional integration of grafted neurons differentiated from stem cells into the host injured neuronal circuitry has been a major challenge in cell therapy strategies for brain repair (Palma-Tortosa et al., 2021). Even though other cell types or mechanisms may provide modest clinical improvements, neuronal replacement and reconstruction of the damaged area are crucial for an optimal and long-term recovery. This process entails three important aspects (Figure 1): (1) the generation of specific neuronal subtypes representative of the damaged brain area, (2) the formation of functional afferent synaptic connections from the host brain to the grafted neurons, and (3) the establishment of functional efferent synaptic contacts from grafted cells to specific areas of the host brain. We previously showed that human skin-derived neural precursors, transplanted into the somatosensory cortex of rats after ischemic stroke, develop a pattern of afferent synaptic connections similar to endogenous neurons located in this area of the brain (Tornero et al., 2017), and form efferent connections with neurons of proper host brain structures (Palma-Tortosa et al., 2020). The ability of grafted cells to functionally integrate in the damaged host brain circuitry has been further demonstrated by other recent studies using animal models (Palma-Tortosa et al., 2021). Interestingly, also transplantation of human cortical neurons onto ex vivo organotypic cultures of adult human cortex proved the establishment of afferent and efferent synapses between host and grafted cells (Grønning Hansen et al., 2020). However, the mechanisms behind functional recovery and integration of new neurons into the brain network still present some unknown aspects that will be discussed in this article (Figure 1).