Exosomes are endogenous nanoparticles secreted by many types of cells and exhibit excellent host biodistribution and biocompatibility. They play important roles in intercellular communication through transfer of mRNA, miRNA, receptors, enzymes, and cytokines. Compared with synthetic virus, lipid, and polymeric nanomedicines which are immunogenic due to their foreign antigen nature and require escape from endosomal-lysosomal pathway for drug delivery, exosomes exhibit significantly reduced immunogenicity and enhanced efficiency for anti-cancer drug delivery attributed to their direct membrane fusion with target cancer cells. By conjugating with targeting ligands, drug carriers can precisely deliver therapeutic agents to cancer cells without harming normal cells. We propose to generate a series of antibody-directed exosome nanomedicines for targeted cancer therapies with enhanced efficiency, safety, and efficacy by engineering natural exosomes with monoclonal antibodies targeting tumor-associated antigens. This will be achieved through three specific aims: (1) development of anti-EphB4 antibodydirected exosome nanomedicines for treatment of head and neck cancer; (2) generation of targeted exosome-based drug delivery system using anti-EGFR antibodies for the therapy of colorectal cancer; (3) design of engineered exosome nanoparticles targeting refractory metastatic breast cancer by bi-specific antibodies binding HER2 and HER3 receptors. The generated antibodydirected exosomes encapsulated with RNAs, chemotherapies, and proteins can allow selective delivery of therapeutic agents to the cytosol of target tumor cells with high efficiency and provide innovative and highly potent nanomedicines for targeted cancer therapies. Translating these novel targeted cancer therapies to exploratory clinical studies in humans will lead to practical applications, benefitting patients with head and neck, colorectal, and metastatic refractory breast cancer, as well as patients with other epithelial cancers.