The ability to exert control over lipid properties, including structure, charge, function, and self-assembly characteristics is a powerful tool that can be implemented to achieve a wide range of biomedical applications. Examples in this arena include the development of caged lipids for controlled activation of signaling properties, metabolic labeling strategies for tracking lipid biosynthesis, lipid activity probes for identifying cognate binding partners, approaches for in situ membrane assembly, and liposome triggered release strategies. In this Account, we describe recent advancements in the latter area entailing the development of stimuli-responsive liposomes through programmable changes to lipid self-assembly properties, which can be harnessed to drive the release of encapsulated contents toward applications including drug delivery. We will focus on an emerging paradigm involving liposomal platforms that are sensitized toward chemical agents ranging from metal cations to small organic molecules that exhibit dysregulation in disease states. This has been achieved by developing synthetic lipid switches that are designed to undergo programmed conformational changes upon the recognition of specific target analytes. These structural alterations are leveraged to perturb the packing of lipids within the membrane and thereby drive the release of encapsulated contents.We provide an overview of the inspiration, design, and characterization of liposomes that selectively respond to wide-ranging target analytes. This series of studies began with the development of calcium-responsive liposomes utilizing a lipid switch inspired by sensors including indo-1. Following this successful demonstration, we next showed that the selectivity of the lipid switch could be altered among different metal cations by producing a liposomal platform for which release is induced through zinc binding. Our next goal was to develop metabolite-responsive liposomes in which switching is driven by molecular recognition events involving phosphorylated small molecules. In this work, screening of lipid switches designed to interact with phosphorylated metabolites led to the identification of liposomal formulations that selectivity release contents in the presence of adenosine triphosphate (ATP). Finally, we were able to modulate the metabolite selectivity by rationally designing a modified lipid switch structure that is activated through complexation of inositol-(1,4,5)-trisphosphate (IP3). These projects show the progression of our approaches for liposome release triggered by molecular recognition principles, building from ion-responsive lipid switches to structures that are activated by small molecules. These "smart" liposomal platforms provide an important addition to the toolbox for controlled cargo release since they respond to ions or small molecules that are commonly overproduced by diseased cells.