OVER the past 30 years, heart rate variability (HRV) has become a central topic in physiological signal analysis, serving as a vital noninvasive indicator of cardiovascular and autonomic system function, with direct connections to respiratory, central nervous and metabolic dynamics. A Medline search reveals more than 8000 papers on different aspects of HRV during this period, covering physiological modeling and interpretation, diagnostic tools in major pathological states such as ischemia and myocardial infarction, heart failure, hypertension, diabetes and other pathologies involving autonomic and central nervous systems, in ambulatory patient monitoring, in intensive care unit and anesthesia level measurement, in sports and space medicine, as well as for the detection of stress level and environmental effects. Nearly a decade ago, the European Society of Cardiology and the North American Society of Pacing and Electrophysiology took the initiative of supporting a Task Force which issued a seminal paper: “Heart rate variability: standards of measurement, physiological interpretation and clinical use” (Circulation 1996;93:1043–1065). The fact that this paper is the third most cited in Circulation suggests that HRV is not only an interesting and reliable quantitative approach to physiological analysis, but also a widely used clinical tool. In fact, practically all 24h-Holter elctrocardiogram (ECG) recording systems have their own modules for the calculation of long and short-term HRV parameters both in time and in frequency domains. The same is true for the surveillance of critical patients in intensive and coronary care units where objective indicators of HRV may contribute to a better treatment. Applications to ECG diagnostic equipment are increasing in recent years for cardiovascular diagnosis, as well as for assessing therapeutic effects. Further, fetal ECG monitoring systems are incorporating HRV as a measure of fetal distress for better surveillance in the perinatal period. Various applications are also being proposed in the post-partum period, as well as for monitoring ECG and heart rate characteristics in the early months of life, especially in those considered at risk for sudden infant death syndrome (SIDS). Autonomic parameters are also considered clinically useful in many neurological disorders such as in dementias, in Parkinson’s disease, in multiple sclerosis, as well as for a better detection of sleep stages and sleep disordered breathing. There is increasing interest in using HRV during renal dialysis for the prevention of hypotensive episodes. However, a major challenge is to demonstrate the utility and clinical implications of specific measures of HRV in diagnosis and monitoring so that such measures become part of routine patient care.