The conversion of phosphatidylethanolamine to phosphatidylcholine was first reported in rat liver microsomes by Bremer and Greenberg. The reaction requires three successive methylations of the ethanolamine moiety by S-adenosylmethionine. The highest activity for this enzyme has been found in liver microsomes and the enzyme from rat liver was recently solubilized and partially purified. Although the activity is highest in liver, it is the minor pathway in this tissue for the synthesis of phosphatidylcholine. The enzyme has recently been identified in bovine adrenal medulla and reports exist on the activity of phosphatidylethanolamine methyltransferase in erythrocyte ghosts, reticulocyte ghosts and mammary gland membranes. In view of the relatively minor importance of the methylation pathway in phosphatidylcholine biosynthesis in liver, we were intrigued by the reports of significant physiological changes attributed to phospholipid methylation. Calculations reported here show that this enzymatic activity in reticulocytes, erythrocytes and mammary gland membranes is 0.1% of that observed in liver microsomes. Furthermore, in conditions where marked changes in microviscosity of the erythrocyte membrane were observed, only extremely small amounts of phosphatidylethanolamine were methylated. For these and other reasons, there is considerable doubt that methylation of phosphatidylethanolamine could account for the many physiological responses attributed to this activity.