Provided here is a comprehensive examination of the basic and clinical condition of three innovative and promising approaches to cancer therapy, which may support or even substitute chemotherapy: differentiation, immunomodulation, and inhibition of angiogenesis. Differentiation shouldnormalize neoplastic cells and make them compatible with the host. Its feasibility with retinoids, interferons, chemotherapeutic and other agents is discussed. Modulation by biological agents, cytotoxic effector cells and drugs is considered in attempts to boost endogenous antitumour defenses and/or to render neoplastic cells more susceptible to the immune attack of the host. Finally, the important aspect of interfering with tumour blood vessel development and function is taken into account. Consideringthe importance that chemotherapy has in cancer treatment and in view of a more and more integrated strategy, the relationship between the aforementioned approaches and chemotherapeutic agents and chemoresistance is treated in detail.