Sleep inertia (SI) defines a period of transitory hypovigilance, confusion, disorientation of behavior and impaired cognitive and sensory-motor performance that immediately follows awakening. SI, the cognitive and behavioral correlate of the transition from sleep to wakefulness, has been incorporated in several models of sleep and vigilance regulation. Monitoring of several physiological parameters during the awakening period clearly indicate that this transition process is very slow. On the cognitive and behavioral side, SI has relevant operational implications. SI is one of the most serious contraindications to the use of napping during quasi-continuous operations if the individual may be required to perform complex tasks immediately after sudden awakening at unpredictable times. The studies on SI modulating factors showed that SI is strongly affected by slow wave sleep amount and sleep depth, while the outcomes concerning the modulation of SI by circadian factors are not consistent. Cognitive tasks involving high attentional load seem to be much more affected by SI than simple motor ones, performance accuracy being more impaired than speed. Finally, some possible countermeasures against the detrimental effects of SI to be applied in operational settings have been provided.