Stroke is a leading cause of long-term disability worldwide. Its highly complex pathogenesis is characterized by a deleterious cycle of deregulated processes at the neurovascular unit. Astrocytes that represent an important neurovascular unit component are critical to early protection of nervous tissue post-stroke. However, astrocyte activation (termed astrogliosis) in response to ischemia becomes increasingly dysregulated and maladaptive with time and majorly interferes with long-term functional recovery. Given this dualistic nature, a better understanding of molecular key players involved in astrocyte activation and their communication with other neurovascular unit cell types may aid in designing strategies for improved stroke recovery. In this regard, the bioactive phospholipid sphingosine-1-phosphate (S1P) provides an interesting target. Specifically, S1P receptors yielded first promising results.