ABSTRACT Congenital adrenal hyperplasia (CAH) is a form of adrenal insufficiency characterized by impaired cortisol synthesis and excessive adrenal androgen production. Children with CAH under the recommended oral hydrocortisone therapy are repeatedly exposed to the undesirable states of hypocortisolemia and hypercortisolemia. Hypocortisolemia triggers increased production of 17-hydroxyprogesterone (17OHP) and adrenal androgen (androstenedione; D4A), which can lead premature fusion of the growth plates, genital virilization, precocious puberty, adrenal rests, polycystic ovarian syndrome and infertility. Hypercortisolemia also has untoward long term effects, such as osteoporosis, short stature, and increased risk for developing metabolic syndrome-related atherosclerotic cardiovascular disease in adult life. Current oral hydrocortisone therapy is suboptimal as it does not replicate the pulsatile daily patterns of both circadian and ultradian cortisol secretion rhythms. As such, even patients on physiological doses experience adverse outcomes. Therefore, an improved and personalized drug delivery system that more closely replicates physiological pulsatile cortisol secretion and limits periods of hypo- and hypercortisolemia in children is needed. Our long term goal is to improve clinical outcomes in children with CAH through optimizing the dosing and scheduling of replacement therapy and avoid the hyperandrogenemia that is specific to CAH. This study's objective is to demonstrate that pulsatile SQHC pump delivery more closely replicates circadian and ultradian rhythms of cortisol and improves control of adrenal androgens. Our study's rationale is that cortisol profiles more consistent with physiologic rhythms of cortisol secretion will produce better health outcomes. Our specific aim is to design and implement an individualized pulsatile SQHC pump regimen that will more closely mimic cortisol circadian and ultradian rhythms in order to reduce the length of time a patient experiences hyper- and hypocortisolemia, and extend the duration of time 17OHP and D4A serum concentrations remain in an acceptable range. This is the first clinical trial in children with CAH that uses a pulsatile SQHC delivery system. Our approach is innovative as it is a substantive departure from the standard of care that could not only significantly improve long-term outcomes of patients with CAH, but also alter our fundamental approach to glucocorticoid dosing of patients with adrenal insufficiency of other etiologies, thus spurring development of novel methods of hormonal drug delivery, and stimulating new lines of investigation in physiological systems with tightly controlled feedback loops.