Immunotoxins are therapeutic agents with a high degree of specificity and unique mechanism of action. An immunotoxin is a chimeric protein consisting of a targeting moiety linked to a toxin. The targeting moiety selectively binds to a tumor cell and targets it for death via the attached toxin. Generally, immunotoxins are specifically potent against cancer cells in vitro and in animal models of human malignancies. However, immunotoxins can be limited clinically by immunogenicity, toxicity, and instability. In this review, we offer ways to overcome these limitations to create "ideal immunotoxins" for cancer therapy. These include producing single chain targeting/toxin fusion proteins of fully human origin that are extracellularly stable but once internalized, can be cleaved by intracellular proteases to free the toxin and facilitate its translocation to the cytosol.