Abstract Metastases are hard to detect and treat, and they cause most cancer-related deaths. The relative lack of therapies targeting metastases represents a major unmet clinical need. The extracellular matrix (ECM) forms a major component of the tumor microenvironment in both primary and metastatic tumors, and certain ECM proteins can be selectively and abundantly expressed in tumors. Nanobodies against ECM proteins that show selective abundance in metastases have the potential to be used as vehicles for delivery of imaging and therapeutic cargoes. Here, we describe a strategy to develop phage-display libraries of nanobodies against ECM proteins expressed in human metastases, using entire ECM-enriched preparations from triple-negative breast cancer (TNBC) and colorectal cancer metastases to different organs as immunogens. In parallel, LC-MS/MS-based proteomics were used to define a metastasis-associated ECM signature shared by metastases from TNBC and colorectal cancer, and this conserved set of ECM proteins was selectively elevated in other tumors. As proof of concept, selective and high-affinity nanobodies were isolated against an example protein from this signature, tenascin-C (TNC), known to be abundant in many tumor types and to play a role in metastasis. TNC was abundantly expressed in patient metastases and widely expressed across diverse metastatic sites originating from several primary tumor types. Immuno-PET/CT showed that anti-TNC nanobodies bind TNBC tumors and metastases with excellent specificity. We propose that such generic nanobodies against tumors and metastases are promising cancer-agnostic tools for delivery of therapeutics to tumor and metastatic ECM. Significance: Nanobodies specific for extracellular matrix markers commonly expressed in primary tumors and metastases are promising agents for noninvasive detection of tumors and metastases and potential tools for targeted therapy.