Customized generation of 3D functional building blocks is crucial for bottom-up tissue engineering. Currently, high throughput production, high survival rates, and well-controlled shapes are considered as three major challenges in fabricating microgels. Here, an optofluidic maskless lithography system that combines digital micromirror device based 3D printing and microfluidic technologies for fabricating 3D functional microgels, is presented. With this system, 3D microgels can be custom designed online and manufactured modularly in a microfluidic device. The fabrication process is based on shadowed light, highly flexible, and requires no physical masks. Furthermore, cells in microgels exhibit features that are more similar to the complex in vivo conditions, including morphology, proliferation, and drug resistance.