The Easson-Stedman hypothesis provided the rationale for the first studies of drug design for the alpha(1)-adrenergic receptor. Through chemical modifications of the catecholamine core structure, the need was established for a protonated amine, a beta-hydroxyl on a chiral center, and an aromatic ring with substitutions capable of hydrogen bonding. After the receptors were cloned and three alpha(1)-adrenergic receptor subtypes were discovered, drug design became focused on the analysis of receptor structure and new interactions were uncovered. It became clear that alpha(1)- and beta-adrenergic receptors did not share stringent homology in the ligand-binding pocket but this difference has allowed for more selective drug design. Novel discoveries on allosterism and agonist trafficking may be used in the future design of therapeutics with fewer side effects. This review will explore past and current knowledge of the structure-function of the alpha(1)-adrenergic receptor subtypes.