Abstract: Amatoxins, as well as antibody-drug conjugates (ADCs) comprising an amatoxin are provided, as well as compositions and methods of using the same. The compositions and methods provided herein can be used for cancer therapy. They can also be used to prepare a patient for hematopoietic stem cell transplant therapy and to improve the engraftment of hematopoietic stem cell transplants by selectively depleting endogenous hematopoietic stem cells prior to the transplant procedure. Methods and compositions for the treatment of various hematopoietic diseases, metabolic disorders, cancers, and autoimmune diseases, as well as prevention of graft-versus-host-disease (GVHD), are provided.