With advances in high-throughput, large-scale in vivo measurement and genome modification techniques at the single-nucleotide level, there is an increasing demand for the development of new technologies for the flexible design and control of cellular systems. Computer-aided design is a powerful tool to design new cells. Whole-cell modeling aims to integrate various cellular subsystems, determine their interactions and cooperative mechanisms, and predict comprehensive cellular behaviors by computational simulations on a genome-wide scale. It has been applied to prokaryotes, yeasts, and higher eukaryotic cells, and utilized in a wide range of applications, including production of valuable substances, drug discovery, and controlled differentiation. Whole-cell modeling, consisting of several thousand elements with diverse scales and properties, requires innovative model construction, simulation, and analysis techniques. Furthermore, whole-cell modeling has been extended to multiple scales, including high-resolution modeling at the single-nucleotide and single-amino acid levels and multicellular modeling of tissues and organs. This review presents an overview of the current state of whole-cell modeling, discusses the novel computational and experimental technologies driving it, and introduces further developments toward multihierarchical modeling on a whole-genome scale.