Background Stress is defined as a state of threatened or perceived as threatened homeostasis. A broad spectrum of extrinsic or intrinsic, real or perceived stressful stimuli, called stressors', activates a highly conserved system, the stress system', which adjusts homeostasis through central and peripheral neuroendocrine responses. Inadequate, excessive or prolonged adaptive responses to stress may underlie the pathogenesis of several disease states prevalent in modern societies. The development and severity of these conditions primarily depend on the genetic vulnerability of the individual, the exposure to adverse environmental factors and the timing of the stressful event(s), given that prenatal life, infancy, childhood and adolescence are critical periods characterized by increased vulnerability to stressors. Materials and methods We conducted a systematic review of original articles and reviews published in MEDLINE from 1975 through June 2016. The search terms were childhood stress', pediatric stress', stress and disorders' and stress management'. Results In this review, we discuss the historical and neuroendocrine aspects of stress, and we present representative examples of paediatric stress system disorders, such as early-life adversity, obesity and bullying. We also discuss the adverse impact of a socio-economic crisis on childhood health. The tremendous progress of epigenetics has enabled us to have a deeper understanding of the molecular mechanisms underlying paediatric stress-related disorders. Conclusions The need for early successful stress management techniques to decrease the incidence of paediatric stress-related diseases, as well as to prevent the development of several pathologic conditions in adolescence and adulthood, is imperative.