A thermoneutral environment is important for many human physiological studies. The thermoneutral zone (TNZ) is defined as the range of ambient temperatures without regulatory changes in metabolic heat production or evaporative heat loss. Many factors influence the thermoneutral zone, such as body composition, clothing, energy expenditure, age and gender. These factors have the potential to introduce bias in study results and therefore need to be taken into consideration in many metabolic studies or studies on obesity, medical conditions, thermal comfort or vigilance. Given new developments on the TNZ combined with historical views the aim of this review is to 1) provide insight in how the human TNZ is affected by internal and external factors, 2) indicate how skin blood flow characteristics could be used as an objective criterion for determining whether someone is in the thermoneutral zone, 3) explain implications of the TNZ on metabolic studies and 4) indicate future directions to enhance understanding of the TNZ, especially for the elderly and obese.