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The conformation of oxytocin is related to the evolution and to some of the biological activities of neurophypophyseal hormonal peptides. On the basis of the three-dimensional structure, positions 3, 4, 7, and 8 are the only loci at which naturally occurring neurohypophyseal peptides may be expected to differ. The side chains of these amino-acid residues are the primary determinants of the differential specificity in interactions between neurohypophyseal hormones and their receptors. THERE ARE THREE GENERAL GROUPS OF STRUCTURAL MODIFICATIONS OF NEUROHYPOPHYSEAL HORMONES WHICH CAN BE CORRELATED WITH SPECIFIC CHANGES IN BIOLOGICAL ACTIVITY: (a) those affecting the stabilization of the backbone of the peptide, which would extensively perturb the spatial relationships among all the constituent amino acids and hence, affect both affinity and intrinsic activities uniformly; (b) those which, while retaining the stability of the backbone conformation, alter the steric environment and charge distribution of limited surface areas, and thereby can affect affinity and intrinsic activity differentially; and (c) those changing the steric and electronic requirements of moieties comprising the active surface of the neurohypophyseal peptide, without perturbing the peptide backbone of the hormone molecule and, hence, affecting intrinsic activity without altering affinity.