In this special issue to celebrate the 30th anniversary of the Uruguayan Society for Neuroscience (SNU), we find it pertinent to highlight that research on glial cells in Uruguay began almost alongside the history of SNU and contributed to the understanding of neuron-glia interactions within the international scientific community. Glial cells, particularly astrocytes, traditionally regarded as supportive components in the central nervous system (CNS), undergo notable morphological and functional alterations in response to neuronal damage, a phenomenon referred to as glial reactivity. Among the myriad functions of astrocytes, metabolic support holds significant relevance for neuronal function, given the high energy demand of the nervous system. Although astrocytes are typically considered to exhibit low mitochondrial respiratory chain activity, they possess a noteworthy mitochondrial network. Interestingly, both the morphology and activity of these organelles change following glial reactivity. Despite receiving less attention compared to studies on neuronal mitochondria, recent studies indicate that mitochondria play a crucial role in driving the transition of astrocytes from a quiescent to a reactive state in various neurological disorders. Notably, stimulating mitochondria in astrocytes has been shown to reduce damage associated with the neurodegenerative disease amyotrophic lateral sclerosis. Here, we focus on studies supporting the emerging paradigm that metabolic reprogramming occurs in astrocytes following damage, which is associated with their phenotypic shift to a new functional state that significantly influences the progression of pathology. Thus, exploring mitochondrial activity and metabolic reprogramming within glial cells may provide valuable insights for developing innovative therapeutic approaches to mitigate neuronal damage. In this review, we focus on studies supporting the emerging paradigm that metabolic reprogramming occurs in astrocytes following damage, which is associated with their phenotypic shift to a new functional state that significantly influences the progression of pathology. Thus, exploring mitochondrial activity and metabolic reprogramming within glial cells may provide valuable insights for developing innovative therapeutic approaches to mitigate neuronal damage.