Lysophosphatidic acid (LPA; monoacyl-glycerol-3-phosphate) and sphingosine 1-phosphate (S1P) are bioactive lysophospholipids that regulate critical biological functions and disease processes. LPA and S1P act on distinct G protein-coupled receptors (GPCRs) that initiate multiple signaling cascades in many cell types. There are six known LPA receptors (LPAR1–6) and five for S1P (S1PR1–5). LPAR1-3 and S1PR1–5 constitute the Edg subfamily of GPCRs, whereas LPAR4–6 are more closely related to purinergic receptors. LPA signaling is critical to such diverse processes as vascular and neural development, lymphocyte homing (Kanda et al., 2008), and hair follicle development (Inoue et al., 2011) and is implicated in pulmonary fibrosis (Tager et al., 2008), neuropathic pain, pruritus, fetal hydrocephalus, and tumor progression. S1P signaling is essential for vascular development and endothelial integrity and plays key roles in the immune, central nervous, and cardiovascular systems (Blaho and Hla, 2011; Rivera et al., 2008). Though LPA and S1P use similar signaling pathways, their biosynthetic routes are quite distinct. Bioactive LPA is produced extracellularly from more complex phospholipids by specific exo/ectophospholipases. In contrast, S1P is mostly synthesized intracellularly by sphingosine kinases and then exported across the plasma membrane. LPA and S1P are present in physiologically relevant concentrations in the circulation; they are rapidly turned over by cell-associated lipid phosphate phosphatases (LPPs). Plasma S1P regulates vascular barrier function; the role of plasma LPA is less well understood. This SnapShot summarizes the LPA/S1P biosynthetic pathways and highlights selected biological actions of either lipid.