Lysophospholipids are lipid molecules that are receiving growing attention because, in addition to their structural function in the cell membrane, they are now regarded as important regulators for diverse biological functions through activation of specific receptors. These receptors have been characterized during the last two decades as G protein-coupled receptors (GPCRs) and, among them, two families stand out: lysophosphatidic acid (LPA_1–6) and sphingosine 1-phoshate (S1P_1–5) receptors. Despite their interest, the high structural similarity between them has restrained the development of selective and high affinity ligands and therefore the elucidation of the role of these receptors in the central nervous system (CNS). This review provides an overview about the different LPA receptors with a special focus on the LPA₁ subtype from a medicinal chemistry perspective. It summarizes the most recent developments in the search for selective and specific agonists and antagonists of the LPA₁ receptor and highlights their current status in the drug development pipeline.