The widespread availability of high-performance computing and accurate and realistic computer simulation techniques has stimulated the development of computational anthropomorphic models of both the anatomy and physiological functions of humans and laboratory animals. These simulation tools have been applied to different medical imaging modalities including ultrasound, single photon emission computed tomography, positron emission tomography, X-ray computed tomography, magnetic resonance imaging, optical imaging, and multimodality imaging with various combinations of the above. This paper reviews the fundamental and technical challenges and future directions of developing computational models of normal and abnormal human anatomy and physiological functions, with a particular focus on their applications to biomedical imaging and radiation dosimetry calculations. The combination of accurate and realistic computer generated models of human and laboratory animals, radiation sources and distributions, transport of radiation through biological tissues, characteristics of the imaging system, and physics of the image formation process allows accurate and realistic simulation of biomedical imaging data and radiation dose distributions that are ever closer to those obtained from clinical and experimental laboratory animal studies. These simulation tools and techniques will provide an increasingly important contribution and impact in the future of biomedical imaging and dosimetry calculations.