Sleep disturbance and sleep disorders affect millions of Americans and are commonly found with other existing medical conditions including cardiovascular disease, chronic pain, diabetes, and neurological disorders. To better understand the comorbidities of sleep disturbance and their negative outcomes, we need to first understand basic sleep function. Current biomedical research has not been able to adequately explain sleep function, and the subject remains controversial. Adaptive processes, such as synaptic plasticity, learning, and memory, are sensitive to sleep loss, which may provide important clues for identifying the physiological function of sleep. Cellular and molecular processes that are critical for sleep function within nervous tissue also may not be restricted to neurons, but may include glial cells, which are known to regulate metabolism, sleep, and cognitive function. Changes in neuronal-glial interactions, particularly around synapses related to activity- and energy-dependent demands during wakefulness, are therefore key sites to investigate the functional aspects of sleep. Here, we propose studies in phylogenetically diverse species that integrate the circadian rhythm of rest-activity cycles with changes in sleep need. We also provide novel avenues for tackling testable questions related to evolutionarily conserved cellular and molecular mechanisms underlying activity- dependent changes in synaptic activity that are sensitive to sleep and are critical for cognitive function.