In vivo-like drug responses are observed in three-dimensional culture but frequently not in two-dimensional culture, indicating that drug response may be a function of tissue architecture. Alexis Carrel introduced that in vitro culture of tissues in the beginning of the century utilizing a culture system that allowed the three-dimensional growth of tissues. Leighton improved upon this system by developing a substrate of sponge matrices. Other methods of three-dimensional culture include collagen gels and what are known as organ culture systems on filters or meshes. In addition, cell suspensions can be converted into multicellular spheroids, another form of three-dimensional culture. Comparison of the three-dimensional culture methods with two-dimensional culture methods has shown critical differences in drug response. The in vivo mechanism of drug resistance may involve alterations in cell-cell interaction which may occur in three-dimensional culture as opposed to monolayer culture.