Investigations of the topography of glycerolipid synthetic enzymes within the transverse plane of microsomal vesicles indicated an exclusive cytoplasmic surface location of active sites. Evidence was derived from studies employing proteases and other impermeant inhibitors, from investigations of latency and substrate permeation, and from localization of products. These studies strongly suggest a total asymmetric synthesis of glycerolipids on the cytoplasmic surface of the endoplasmic reticulum. The data are critically reviewed, emphasizing the importance of appropriate controls for topographical studies of microsomal enzymes. The limited data on the location and topography of other enzymes of complex lipid metabolism in microsomes, peroxisomes, mitochondria, and other membranes are also reviewed. These new findings have important implications for the processes of "lipid topogenesis" which encompass complex lipid synthesis, the integration of lipids into membranes, and lipid translocation across membranes. Later events of lipid topogenesis involve lipid movement to other membranes and structures, the sorting of complex lipids from each other to assemble structures of distinct lipid composition, and the formation and maintenance of lipid asymmetry.