Abstract The widespread availability of high-performance computing and popularity of simulations stimulated the development of computational anthropomorphic models of the human anatomy for medical imaging modalities and dosimetry calculations. The widespread interest in molecular imaging spurred the development of more realistic three- to five-dimensional computational models based on the actual anatomy and physiology of individual humans and small animals. These can be defined by either mathematical (analytical) functions or digital (voxel-based) volume arrays (or a combination of both), thus allowing the simulation of medical imaging data that are ever closer to actual patient data. The paradigm shift away from the stylized human models is imminent with the development of more than 30 voxel-based tomographic models in recent years based on anatomical medical images. We review the fundamental and technical challenges of designing computational models of the human anatomy, and focus particularly on the latest developments and future directions of their application in the simulation of radiological imaging systems and dosimetry calculations.