Plasmodium, the causative agent of malaria, is an obligate, intracellular, eukaryotic cell that invades, replicates, and differentiates within hepatocytes and erythrocytes. Inside a host cell, a second membrane delineates the developing pathogen in addition to the parasite plasma membrane, resulting in a distinct cellular compartment, termed parasitophorous vacuole (PV). The PV membrane (PVM) constitutes the parasite–host cell interface and is likely central to nutrient acquisition, host cell remodeling, waste disposal, environmental sensing, and protection from innate defense. Over the past two decades, a number of parasite-encoded PVM proteins have been identified. They include multigene families and protein complexes, such as early-transcribed membrane proteins (ETRAMPs) and the Plasmodium translocon for exported proteins (PTEX). Nearly all Plasmodium PVM proteins are restricted to this genus and display transient and stage-specific expression. Here, we provide an overview of the PVM proteins of Plasmodium blood and liver stages. Biochemical and experimental genetics data suggest that some PVM proteins are ideal targets for novel anti-malarial intervention strategies.