Provided here is a comprehensive examination of the basicand clinical condition of three innovative and promisingapproaches to cancer therapy, which may support or evensubstitute chemotherapy: differentiation, immunomodulation, and inhibition of angiogenesis. Differentiation shouldnormalize neoplastic cells and makethem compatible with the host. Its feasibility withretinoids, interferons, chemotherapeutic and other agents isdiscussed. Modulation by biological agents, cytotoxiceffector cells and drugs is considered in attempts toboost endogenous antitumour defenses and/or to renderneoplastic cells more susceptible to the immune attack ofthe host. Finally, the important aspect of interfering withtumour blood vessel development and function is takeninto account. Consideringthe importance that chemotherapy has in cancertreatment and in view of a more and more integratedstrategy, the relationship between the aforementionedapproaches and chemotherapeutic agents and chemoresistanceis treated in detail.