The efficacy in cancer treatment of monoclonal antibodies or other macromolecules bound to radionuclides, chemotherapeutic agents, toxins, enzymes, growth factors, or effector antibodies has been limited by their inability to reach their target in vivo in adequate quantities. Heterogeneity of tumor-associated antigen expression alone has failed to explain the nonuniform uptake of antibodies. As a result, only in recent years have the peculiarities of tumor physiology been recognized as determinants of antibody distribution. Three physiological barriers responsible for the poor localization of macromolecules in tumors have been identified: (a) heterogeneous blood supply; (b) elevated interstitial pressure; and (c) large transport distances in the interstitium. The first barrier limits the delivery of blood-borne molecules to well-perfused regions of a tumor; the second barrier reduces extravasation of fluid and macromolecules in the high interstitial pressure regions and also leads to an experimentally verifiable, radially outward convection in the tumor periphery which opposes the inward diffusion; and the third barrier increases the time required for slowly moving macromolecules to reach distal regions of a tumor. Binding of antibody to an antigen further lowers the effective diffusion rate of the antibody by reducing the amount of mobile antibody. Due to micro- and macroscopic heterogeneities in tumors, the relative magnitude of each of these barriers would vary from one location to another and from one day to the next in the same tumor and from one tumor to another. If the genetically engineered macromolecules, e.g., lymphokines, and other new modalities, e.g., killer lymphocytes, as well as low molecular weight cytotoxic agents, are to fulfill their clinical promise, methods must be developed to overcome these physiological barriers. Some of these methods are discussed, and situations wherein these barriers may not be a problem are pointed out.