Regeneration of rat adrenals was studied after bilateral enucleation to determine whether there is a neural component mediating this process as there is in compensatory adrenal growth after unilateral adrenalectomy. Regeneration was approximately 50% complete (based on criteria of wet weight and DNA content) by 10 days after enucleation; at this time circulating ACTH levels were twice as high in enucleates as in sham-operated controls, but corticosterone levels were normal. Regeneration was apparently complete at sometime between 3 and 6 weeks and circulating ACTH and corticosterone levels were normal at these times compared to controls. Unilateral adrenal enucleation resulted in compensatory growth of the opposite gland, not regeneration of the enucleated gland. Unilateral hypothalamic hemi-islands made with a Halász knife resulted in bilateral augmentation of adrenal regeneration at 10 days and 6 weeks. From these results we conclude that adrenal regeneration after bilateral enucleation occurs by different afferent and efferent mechanisms than compensatory adrenal growth after unilateral adrenalectomy. Additional studies were performed in rats 3 and 6 weeks after adrenal enucleation to test whether the adrenal medulla participates either in compensatory adrenal growth or in the augmented ACTH response to ether vapors observed in unilaterally adrenalectomized rats. Normal compensatory adrenal growth occurred 3 days after unilateral adrenalectomy in rats bilaterally enucleated 6 weeks earlier. Prior enucleation did not inhibit the increased ACTH response of unilaterally adrenalectomized rats to ether. Therefore, the adrenal medulla does not mediate compensatory adrenal growth or the augmented ACTH response of unilaterally adrenalectomized rats to ACTH-releasing stimuli