Masaaki Uematsu1 and Jeremy M. Baskin1,2 1Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York 14853, USA 2Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA Correspondence: jeremy.baskincornell.edu

As the products of complex and often redundant metabolic pathways, lipids are challenging to measure and perturb using genetic tools. Yet by virtue of being the major constituents of cellular membranes, lipids are highly regulated in space and time. Chemists have stepped into this methodological void, developing an array of techniques for the precise quantification and manipulation of lipids at the subcellular, organelle level. Here, we survey the landscape of these methods. For measuring lipids, we summarize the use of metabolic labeling and click chemistry tagging, photoaffinity labeling, isotopic tagging for Raman microscopy, and chemoenzymatic labeling for tracking lipid production and interorganelle transport. For perturbing lipids, we describe synthetic photocaged lipids and membrane editing approaches using optogenetic enzymes for precise manipulation of lipid signaling. Collectively, these chemical and biochemical tools are revealing phenomena and mechanisms underlying lipid functions at the subcellular level.