This paper presents the background and history of the virtual human Santos™ developed by the Virtual Soldier Research (VSR) Program at The University of Iowa. The early virtual human environment was called Mira™. This 15-degree-of-freedom (DOF) upper-body model with posture and motion prediction was funded by John Deere Inc. and US Army TACOM Automotive Research Center. In 2003 US Army TACOM began funding VSR to develop a new generation of virtual humans called Santos (109 DOFs), which was to be another generation of Mira. Later on, Caterpillar Inc., Honda R&D North Americas, Natick Soldier System Center, and USCAR (GM, Ford, and Chrysler) joined the VSR partnership. The objective is to develop a new generation of digital humans comprising realistic human models including anatomy, biomechanics, physiology, and intelligence in real time, and to test digital mockups of products and systems before they are built, thus reducing the significant costs and time associated with making prototypes. The philosophy is based on a novel optimization-based approach for empowering these digital humans to perform, un-aided, in a physics-based world. The research thrusts include the following areas: (1) predictive dynamics, (2) modeling of cloth, (3) hand model, (4) intuitive interface, (5) motion capture, (6) muscle and physiology modeling, (7) posture and motion prediction, (8) spine modeling, and (9) real-time simulation and virtual reality (VR). Currently, the capabilities of Santos include whole-body posture prediction, advanced inverse kinematics, reach envelope analysis, workspace zone differentiation, muscle force and stress analysis, muscle fatigue prediction, simulation of walking and running, dynamic motion prediction, physiologic assessment, a user-friendly interface, a hand model and grasping capability, clothing modeling, thermo discomfort assessment, muscle wrapping and sliding, whole-body vibration analysis, and collision avoidance.