Growing cells in three-dimensional (3D) culture conditions has been in use for several decades. However, neither the interest to use 3D culture methods nor the necessity is fully appreciated until recently. Developments in the ability to design organ-specific media conditions to support the growth of primary or stem or tumor cells in 3D culture conditions have catapulted the field of to a new dimension and the appetite for using 3D culture methods is overshadowing the use of monolayer cultures. For the past 20 years, we have developed and utilized 3D culture and organoid methods to understand epithelial morphogenesis, cell polarity, cancer initiation, and progression and translational cancer research. I will discuss our efforts in developing and using 3D culture methods for tumors and stem cells for modeling and understanding cancer biology. In addition, I will discuss our recent unpublished observations on the use of tumor organoid culture for personalized medicine.