Heart rate variability (HRV), is modulated by the autonomic nervous system (ANS) and is an indicator of clinically relevant cardiovascular phenotypes. Vigilance state and endogenous circadian phase are major modulators of the ANS. Sympathetic activity is higher during wakefulness than in sleep, and, within sleep, the sympathetic contribution is greater in rapid-eye-movement (REM) sleep than in deep non-REM sleep. It has been clearly shown that acute sleep deprivation leads to a greater sympathetic influence on the autonomic control of the heart. Endogenous circadian rhythmicity influences autonomic control of HR and the timing of these endogenous rhythms can be altered by extended sleep/rest episodes and associated changes in photoperiod. Circadian control of the heart is not entirely mediated by the sleep–wake-cycle and autonomous modulations are influenced by the circadian system. During continuous wakefulness under controlled behavioural conditions, HRV is not constant but varies with circadian phase such that global HRV is greatest in the early morning hours with a major cardiovascular event due to abrupt changes in the sympatho-vagal-cardiac control during the transition from sleep to wakefulness. The impact of sleep, wakefulness, and circadian phase on autonomic control of HRV is also of interest because the frequency of acute myocardial infarctions shows a marked circadian variation. Understanding the sources of individual differences in HRV and how these relate to inter-individual differences in sleep and circadian physiology may increase the diagnostic use of HRV and may provide new avenues for preventive therapy especially with novel recording technique using at-home sleep monitoring.