Short peptide sequences of ACTH 1-39 (the ACTH 4-9 analog Org 2766, ACTH 4-10 and its analog BIM 22015, and ACTH 1-13 [alpha-MSH]), which do not stimulate the adrenal cortex, have profound effects on the developing and regenerating neuromuscular system, in neonatal and in adult rats. Both development and regeneration are accelerated, as indicated by improved morphological, electrophysiological, behavioral and biochemical parameters. Regeneration in the central nervous system is problematic but the ACTH peptides may provide protection for CNS neurons, enhance denervation sensitivity or permit compensatory processes which facilitate functional recovery. Neuronal cells in culture respond to ACTH peptides by greater neurite outgrowth, and in some cell types, by increased B-50 expression. In all cases, susceptibility to ACTH peptide treatment varies with cell type, age, the specific peptide administered, its dosage and pattern of administration. External stress and the gender of the animal are additional factors that interact with the neurotrophic actions of the melanocortins.