In the last years, α1 adrenoceptors (α1-AR) have been the subject of intense research, in part because receptor-binding studies and molecular biology have opened up new aspects of understanding but also because of the potential to find new drugs possibly acting toward pathophysiological processes where α1-AR are involved, such as benign prostatic hyperplasia (BPH) or hypertension. At present, arylpiperazines represent one of the most studied classes of molecules with affinity at α1-AR. In fact, a large amount of work has been done and reported, describing synthetic procedures, biological evaluation at both α1-AR and the corresponding subtypes, and structure-activity relationships (SARs). In this paper, a review based on a literature survey aimed at focusing on the structural properties that a compound should possess to show affinity toward α1-AR is presented. Moreover, the identification and optimization of the structural features of a hit compound derived from a pharmacophore-based database search, leading to a new class of arylpiperazinylalkyl pyridazinone derivatives with α1-AR affinity is reported.