This disclosure provides ASCT2-binding molecules, e.g., anti-ASCT2 antibodies, and antigen-binding fragments thereof. In certain aspects, the ASCT2-binding molecules are conjugated to cytotoxic drugs, e.g., ASCT2 antibody-drug conjugates (ADCs). In certain aspects, the anti-ASCT2 antibodies and fragments thereof can be hybridoma-derived murine monoclonal antibodies, and humanized versions thereof. In certain aspects, the ASCT2-binding molecules bind specifically to cells expressing ASCT2, and in some instances, are internalized into the cells. In addition, this disclosure provides compositions and methods for diagnosing and treating diseases or disorders characterized by ASCT2 overexpression, e.g., certain types of cancer. In a particular embodiment, the disclosure provides methods for treating cancer using ASCT2 ADCs.