The intracellular accumulation of amyloid-β (Aβ), which is generated by the proteolytic processing of the amyloid precursor protein (APP), is a hallmark of early Alzheimer's disease (AD) pathogenesis. APP and Aβ have been found in endolysosomal compartments in the cell, and APP has been suggested to traffic onto intraluminal vesicles (ILVs) of endosomes in an endosomal sorting complexes required for transport (ESCRT)-dependent manner. However, it is unclear how the targeting of APP to ILVs affects its processing or the fate of Aβ. Here (p. 2520), Clare Futter and colleagues examined the role of ESCRT-dependent targeting of APP to ILVs with regards to APP degradation and the effects on the intracellular accumulation of Aβ. They showed that in cultured neuronal cells, as well as in the hippocampi of a transgenic AD mouse model, APP localised to ILVs within a subset of multivesicular endosomes and bodies. The authors also found that APP was ubiquitylated and subject to lysosomal degradation. Furthermore, depletion of the early ESCRT components Hrs (also known as Hgf) or Tsg101 prevented the recruitment of APP to ILVs, thereby decreasing its lysosomal targeting, and also resulted in increased intracellular accumulation of Aβ. Taken together, these results demonstrate that ESCRT-dependent targeting of APP to ILVs is important both for APP lysosomal degradation and Aβ secretion, thereby influencing the intracellular accumulation of Aβ at two distinct stages.