Cyp21a2-deficient zebrafish have a number of systemic hallmark features of human 21OHD, including upregulation of the hypothalamic–pituitary–interrenal (HPI) axis, interrenal hyperplasia, pathognomonic steroid hormone profiles, and reduced systemic glucocorticoid-mediated expression of target genes. Here, CYP21A2 is linked to classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency.