Current weight-based approaches to growth hormone (GH) dosing result in dramatic variability in height outcome and insulin-like growth factor (IGF) levels. Optimization of both safety and efficacy is desired; therefore, an intermittent, scheduled titration of GH to maintain serum IGF-I and IGF binding protein (IGFBP)-3 levels within age-dependent normal ranges is physiologically sound and analogous to monitoring other replacement therapies used in pediatric endocrinology, such as in hypothyroidism. Optimal growth-promoting doses differ by individual, and thus surrogate markers such as IGF-I and IGFBP-3 levels are important in the assessment of GH treatment compliance, safety, efficacy, and overtreatment. With the evolution of better prediction models, a new approach that integrates biochemical and auxological parameters will become the standard of care. This approach, studied in large prospective randomized trials, will lead to better patient responses and fewer long-term complications.