Pioneering work demonstrated that an unstable substance isolated from rabbit and pig aortas could relax arterial smooth muscle and inhibit platelet aggregation. Since then, prostacyclin (prostaglandin I2, PGI₂) and its analogs have raised much pharmacological interest. In this review we detail how the PGI₂ signaling pathway is much more complex than was initially anticipated, involving peroxisome proliferator-activated receptors (PPARs), prostaglandin transporters (PGTs), and PGI₂–thromboxane A₂ (TXA₂) receptor (IP TP) heterodimerization. We discuss the distinct affinities of PGI₂ analogs for prostanoid receptors. In addition, we introduce the new direct and indirect pharmacological approaches to targeting the PGI₂ pathway within the systemic circulation, including non-prostanoid agonists of the prostacyclin receptor (IP) and PGT inhibitors, as well as transcutaneous pathways using iontophoresis and nanostructured lipid carriers.