BackgroundDuring a 24-h day, each given period is spent in either sedentary behaviour, sleeping, light physical activity (LPA), or moderate-to-vigorous physical activity (MVPA). In epidemiological research most studies have traditionally analysed the associations of these behaviours in isolation from each other; that is, without taking into account the displacement of time spent in the remaining behaviours. In recent years, there has been a growing interest in exploring how all the behaviours across the energy expenditure spectrum influence health outcomes. A statistical model used to investigate these associations is termed an isotemporal substitution model (ISM). Considering the increasing number of ISM-based studies conducted in all age groups, the present paper aimed to: (i) review and summarise findings from studies that employed ISM in sleep, sedentary behaviour, and physical activity research; (ii) appraise the methodological quality of the studies; and (iii) suggest future research directions in this area.MethodsA systematic search of ten databases was performed. The Newcastle–Ottawa scale was used to assess the methodological quality of the included studies.ResultsFifty-six studies met the inclusion criteria, all being of moderate or high methodological quality. Associations were reported for exchanged time varying from one minute to 120 min/day across the studies, with 30 min/day being the most common amount of time reallocated. In total, three different ISM methodologies were used. The most commonly studied health outcomes in relation to isotemporal substitutions were mortality, general health, mental health, adiposity, fitness, and cardiometabolic biomarkers. It seems that reallocations of sedentary time to LPA or MVPA are associated with significant reduction in mortality risk. Current evidence appears to consistently suggest that reductions in mortality risk are greater when time spent sedentary is replaced with higher intensities of physical activity. For adiposity, it seems that reallocating sedentary time to physical activity may be associated with reduced body mass index, body fat percentage, and waist circumference in all age groups, with the magnitude of associations being greater for higher intensities of physical activity. While there is a relatively large body of evidence reporting beneficial associations between the reallocation of time from sedentary behaviour to LPA or MVPA and cardiometabolic biomarkers among adults, there is a lack of studies among children, adolescents, and older adults. Although some studies investigated general health, mental health, and fitness outcomes, further investigation of these topics is warranted. In general, it seems that the strongest association with health outcomes is observed when time is reallocated from sedentary behaviour to MVPA. Most studies did not account for sleep time, which is a major limitation of the current evidence.ConclusionsThe current evidence indicates that time reallocation between sleep, sedentary behaviour, LPA, and MVPA may be ass...