Ever since Stephen Paget?s 1889 hypothesis, metastatic organotropism has remained one of cancer?s greatest mysteries. In this paper, we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins ?<
sub>
6<
/sub>
?<
sub>
4<
/sub>
and ?<
sub>
6<
/sub>
?<
sub>
1<
/sub>
were associated with lung metastasis, while exosomal integrin ?<
sub>
v<
/sub>
?<
sub>
5<
/sub>
was linked to liver metastasis. Targeting the integrins ?<
sub>
6<
/sub>
?<
sub>
4<
/sub>
and ?<
sub>
v<
/sub>
?<
sub>
5<
/sub>
decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. In conclusion, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.