SimuCell3D is an efficient, open-source program designed to simulate large, three-dimensional (3D) tissues with subcellular resolution. It accounts for cell-based mechanics, growth, proliferation, extracellular matrix (ECM), fluid cavities, nuclei, and non-uniform mechanical properties, particularly in polarized epithelia. The program overcomes the computational limitations of previous models by allowing the simulation of complex cell shapes and large tissue geometries, such as spheroids, vesicles, sheets, and tubes, directly from microscopy images. SimuCell3D enables the study of tissue organization in development and disease, revealing that 3D cell shapes in layered and pseudostratified epithelia are primarily governed by the competition between surface tension and intercellular adhesion. The program's versatility and computational efficiency make it a powerful tool for investigating the mechanical properties and behaviors of cells, providing insights into tissue homeostasis and morphogenesis.SimuCell3D is an efficient, open-source program designed to simulate large, three-dimensional (3D) tissues with subcellular resolution. It accounts for cell-based mechanics, growth, proliferation, extracellular matrix (ECM), fluid cavities, nuclei, and non-uniform mechanical properties, particularly in polarized epithelia. The program overcomes the computational limitations of previous models by allowing the simulation of complex cell shapes and large tissue geometries, such as spheroids, vesicles, sheets, and tubes, directly from microscopy images. SimuCell3D enables the study of tissue organization in development and disease, revealing that 3D cell shapes in layered and pseudostratified epithelia are primarily governed by the competition between surface tension and intercellular adhesion. The program's versatility and computational efficiency make it a powerful tool for investigating the mechanical properties and behaviors of cells, providing insights into tissue homeostasis and morphogenesis.