In this chapter we describe the development of first generation immunotoxins containing ricin and its A chain. The roles of the ligand, linker and toxin in generating highly specific in vivo reagents are discussed. The problems associated with first generation immunotoxins in the clinic, and the subsequent development and performance of second generation reagents are described. Finally, future directions for the successful application of these reagents to the therapy of cancer, autoimmunity, transplantation, and infectious diseases are outlined.