Cerebral plasticity and neurological recovery can be stimulated in the ischemic brain by exogenous pharmacological and cell-based treatments. Neurons, neuroblasts and endothelial cells synergistically interact with each other as a regenerative triad, creating an environment in which neurological recovery takes place. Developmental genetic programs are reactivated. Brain neurons and capillary cells are enabled to sprout, and glial cells support plasticity processes. Until now, the large majority of studies were performed in young, otherwise healthy animals, which lack the risk factors and co-morbidities associated with human stroke. Recent behavioral, histochemical and molecular biological studies have shown that restorative brain responses may differ between young and old animals, and that they are also modulated by vascular risk factors, such as hyperlipidemia and diabetes, which are highly prevalent in ischemic stroke. We claim that age aspects, vascular risk factors and co-morbidities should more intensively be examined in future experimental studies. Confounding effects of age, risk factors and co-morbidities should carefully be considered in clinical proof-of-concept trials.