Adrenergic receptors (ARs) are members of the G-protein-coupled receptor family, which includes α₁ARs, α₂ARs, β₁ARs, β₂ARs, β₃ARs, adenosine, muscarinic, angiotensin, endothelin receptors, and many others that are responsible for a large variety of physiologic effects through G-protein coupling. This review focuses on α₁ARs and their regulation at both the mRNA and protein levels. Currently, three α₁AR subtypes have been characterized both pharmacologically and at the gene level: α_1aAR, α_1bAR, and α_1dAR. These are expressed in a species- and tissue-dependent manner. Mutagenesis approaches have been extremely valuable in the identification of key residues that govern α₁AR ligand binding and signaling. These studies reveal that α₁ARs have evolved an exquisitely sensitive regulation of their activity in which any disruption of the native structure has profound effects on subsequent function and effector coupling. Significant advances have also been made in the elucidation of signaling pathway components, resulting in the identification of novel pathways that can lead to pathologic conditions. Specific topics include mitogen-activated protein kinase , phosphatidylinositol 3-kinase , and G-protein-coupled receptor cross-talk pathways. Within this context, recent studies identifying underlying transcriptional mechanisms involved in the regulation of the α₁AR subtypes is also discussed. Finally, given the potentially important role of α₁ARs in the vasculature, as well as in the pathology of many diseases, such as myocardial hypertrophy and benign prostatic hyperplasia, the clinical relevance of α₁AR distribution, pharmacology, and therapeutic intervention is reviewed.