Purpose of review Protein-based therapeutics have been applied for decades to remove most malignant tumors. Many anti-tumor drugs using antibodies have been developed and put to practical use. However, due to limitations of antibodies such as tolerance, high molecular weight, and poor tissue penetration, new types of fusion proteins have been developed for therapeutic purposes. In this study, we review the recent therapeutic trials and improvements of fusion protein toxins. Recent findings As a targeting moiety, non-Ig scaffolds have not only the advantages of immunoglobulin such as high affinity and selectivity, but also small size, high stability, high yield expression. As a toxic moiety, non-immunologic and highly toxic endogenous proteins of human origin like proapoptotic protein or RNase are challenged. To lessen the adverse reactions of fusion toxins, several therapeutic strategies such as removal of epitopes, increase of serum half-life were developed.