Tumour exosome integrins determine organotropic metastasis. Exosomes from lung-, liver- and brain-tropic tumour cells preferentially fuse with resident cells at their predicted destination, preparing the premetastatic niche. Exosome proteomics revealed distinct integrin expression patterns, with α6β4 and α6β1 integrins associated with lung metastasis and αvβ5 with liver metastasis. Targeting these integrins reduced exosome uptake and metastasis. Exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Clinical data indicate exosomal integrins can predict organ-specific metastasis. Exosomes from different cancer models recapitulate the organ specificity of their cell of origin. Exosome integrins regulate local microenvironments, directing organ-specific colonization. Exosomal integrins determine organotropism by interacting with cell-associated ECM, mediating exosome uptake in specific target organs. Exosomal integrins activate Src and upregulate pro-migratory and pro-inflammatory S100 molecules in specific resident cells. Exosomal integrins can be used as biomarkers to predict metastatic sites. Exosomal integrins and exosome-inducible S100 molecules represent candidates for anti-metastatic combination therapies. Exosomes play a key role in dictating organ-specific metastasis, providing a basis for deciphering the mystery of organotropism.Tumour exosome integrins determine organotropic metastasis. Exosomes from lung-, liver- and brain-tropic tumour cells preferentially fuse with resident cells at their predicted destination, preparing the premetastatic niche. Exosome proteomics revealed distinct integrin expression patterns, with α6β4 and α6β1 integrins associated with lung metastasis and αvβ5 with liver metastasis. Targeting these integrins reduced exosome uptake and metastasis. Exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Clinical data indicate exosomal integrins can predict organ-specific metastasis. Exosomes from different cancer models recapitulate the organ specificity of their cell of origin. Exosome integrins regulate local microenvironments, directing organ-specific colonization. Exosomal integrins determine organotropism by interacting with cell-associated ECM, mediating exosome uptake in specific target organs. Exosomal integrins activate Src and upregulate pro-migratory and pro-inflammatory S100 molecules in specific resident cells. Exosomal integrins can be used as biomarkers to predict metastatic sites. Exosomal integrins and exosome-inducible S100 molecules represent candidates for anti-metastatic combination therapies. Exosomes play a key role in dictating organ-specific metastasis, providing a basis for deciphering the mystery of organotropism.