Stephen Paget first proposed, in 1889, that organ distribution of metastases is a non-random event, yet metastatic organotropism remains one of the greatest mysteries in cancer biology. We demonstrate that exosomes released by lung-, liver- and brain-tropic tumor cells fuse preferentially with resident cells at their predicted destination, such as fibroblasts and epithelial cells in the lung, Kupffer cells in the liver, and endothelial cells in the brain. We found that exosome homing to organ-specific cell types prepares the pre-metastatic niche and that treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumor cells. Proteomic profiling of exosomes revealed distinct integrin expression patterns, where exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting α64 and αv5 integrins decreased exosome uptake and metastasis in the lung and liver, respectively. We demonstrate that exosome uptake activates a cell-specific subset of S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.