In order to understand why cancer develops as well as predict the outcome of pharmacological treatments, we need to model the structure and function of organs in culture so that our experimental manipulations occur under physiological contexts. This review traces the history of the development of a prototypic example, the three-dimensional (3D) model of the mammary gland acinus. We briefly describe the considerable information available on both normal mammary gland function and breast cancer generated by the current model and present future challenges that will require an increase in its complexity. We propose the need for engineered tissues that faithfully recapitulate their native structures to allow a greater understanding of tissue function, dysfunction, and potential therapeutic intervention.