Escherichia coli K-12 is an ideal test bed for pushing forward the limits of our ability to understand cellular systems through computational modeling. A complete understanding will require arrays of mathematical models, a wealth of data from measurements of various life processes, and readily accessible databases that can be interrogated for testing our understanding. Accomplishing this will require improved approaches for mathematical modeling, unprecedented standardization for experimentation and data collection, completeness of data sets, and improved methods of accessing and linking information. Solving the whole cell problem, even for a simple E. coli model cell, will require the concerted efforts of many scientists with different expertise. In this chapter, we review advances in (i) computing for modeling cells, (ii) creating a common language for representing computational models (the Systems Biology Markup Language), and (iii) developing the International E. coli Alliance, which has been created to tackle the whole cell problem.