Whole-cell models which comprehensively predict how phenotypes emerge from genotype promise to enable rational bioengineering and precision medicine. Here, we outline the key principles of whole-cell modeling which have emerged from our work developing bacterial whole-cell models: single-cellularity; functional, genetic, molecular, and temporal completeness; biophysical realism including temporal dynamics and stochastic variation; species-specificity; and model integration and reproducibility. We also outline the whole-cell model construction process, highlighting existing resources. Numerous challenges remain to achieving fully complete models including developing new experimental tools to more completely characterize cells and developing a strong theoretical understanding of hybrid mathematics. Solving these challenges requires collaboration among computational and experimental biologists, biophysicists, biochemists, applied mathematicians, computer scientists, and software engineers.