₁-Adrenergic receptors have been implicated in growth-promoting pathways. A microarray study of individual ₁-adrenergic receptor subtypes (_1A, _1B and _1D) expressed in Rat-1 fibroblasts revealed that epinephrine altered the transcription of several cell cycle regulatory genes, in a direction consistent with the _1A- and _1D-adrenergic receptors mediating G1-S cell cycle arrest, and the _1B- mediating cell-cycle progression. A time-course indicated that in _1A- cells, epinephrine stimulated a G1-S arrest, which began after 8 h of stimulation and maximized at 16 h, at which point was completely blocked with cycloheximide. The _1B-adrenergic receptor profile also showed unchecked cell cycle progression, even under low serum conditions and induced foci-formation. The G1-S arrest induced by _1A- and _1D-adrenergic receptors was associated with decreased cyclin-dependent kinase-6 and cyclin E-associated kinase activities, and increased expression of the cyclin-dependent kinase inhibitor p27^Kip1, all of which were blocked by prazosin. There were no differences in kinase activities and/or expression of p27^Kip1 in epinephrine _1B-AR fibroblasts, although the microarray did indicate differences in p27^Kip1 RNA levels. Cell counts proved the anti-mitotic effect of epinephrine in _1A- and _1D-cells, and indicated that _1B-adrenergic receptor subtype expression was sufficient to cause proliferation of Rat-1 fibroblasts independent of agonist stimulation. Analysis in transfected PC12 cells also confirmed the _1A- and _1B-adrenergic receptor effect. The _1B- subtype native to DDT1-MF2 cells, a smooth muscle cell line, caused progression of the cell cycle. These results indicate that the _1A- and _1D-adrenergic receptors mediate G1-S cell-cycle arrest while _1B-adrenergic receptor expression causes a cell cycle progression and may induce transformation in sensitive cell lines.