Abstract Entamoeba histolytica is a protozoan pathogen and the causative agent of amoebiasis in humans. The species name (histo-: tissue; lytic-: dissolving) derives from the ability to destroy host tissues. E. histolytica trophozoites (“amoebae”) invade the large intestine, causing ulceration and can spread to other tissues (e.g., liver, lungs, brain), causing fatal abscesses. Amoebae possess contact-dependent cell-killing activity that is likely to drive tissue damage, but the mechanism was unclear. We established a new paradigm by discovering that amoebae kill by biting off and ingesting human cell fragments, which we named “amoebic trogocytosis” (trogo-: nibble) (Ralston, et al., Nature, 2014). Building on this discovery, here we propose to delineate its underlying mechanism. Trogocytosis is likely to share features with phagocytosis, since many proteins with roles in phagocytosis are also required for trogocytosis. However, there are emerging hints that aspects of the trogocytosis mechanism are distinct. Thus, we hypothesize that aspects of the trogocytosis mechanism are distinct from phagocytosis. We will apply genetic and transcriptomic approaches to delineate the genes that are shared between trogocytosis and phagocytosis, and those that are specific to each process. Beyond E. histolytica, trogocytosis has far-reaching applications to eukaryotic biology. Several microbial eukaryotes appear to use trogocytosis for cell-killing. In multicellular eukaryotes, trogocytosis is used for cell-killing, cell-cell communication and cell-cell remodeling. Trogocytosis plays roles in the immune system, in the central nervous system, and during development. Therefore, an improved understanding of the mechanism and biology of E. histolytica trogocytosis will have a broad impact beyond amoebiasis. This work is significant and high-impact as it will define the mechanism underlying trogocytosis and how it differs from phagocytosis. Our approaches will also generate valuable new genetic tools. Moreover, our findings will apply directly to amoebiasis pathogenesis, and broadly to other infections and the conserved process of trogocytosis. !