The balance between vasodilator and vasoconstrictor pathways is key to the maintenance of homeostasis and the outcome of disease. In the kidney, prostaglandins (PGs) uphold this balance and regulate renal function: hemodynamics, renin secretion, growth responses, tubular transport processes, and cell fate. With the advent of cyclooxygenase (COX)-2-selective inhibitors, targeted deletions in mice (COX knockouts, PG receptor knockouts), and the discovery of intracrine signaling options for PGs (peroxisome proliferator-activated receptors and perinuclear PGE(2) receptors: EP(1,3,4)), many advances have been made in the study of arachidonic acid metabolites. Although prostacyclin (PGI(2)) is a major product of the COX pathway, there is very little emphasis on its importance to the kidney. This review will discuss PGI(2) biology and its relevance to different aspects of renal disease (growth, fibrosis, apoptosis), highlighting the most significant research from the past decade of PGI(2) literature, what we have learned from other organ systems, while stressing the significance of cross talk between various PGI(2) signaling pathways and its implications for renal health and disease.