Detailed modeling of the free solution electrophoresis of five proteins (bovine alpha-lactalbumin, hen egg white lysozyme, bovine superoxide dismutase, human carbonic anhydrase II, and hen ovalbumin) is carried out within the framework of the continuum primitive model. Protein crystal structures and translational diffusion constants are used to design and parametrize the models. The modeling results are compared with experimental mobilities of protein charge ladders, collections of protein derivatives where the number of charge groups is varied by partial acylation of lysine residues or by amidation of glutamic and aspartic acid residues. The simplest model considered is the Yoon and Kim model of a prolate/oblate ellipsoid with uniform surface potential, electrostatics treated-at the level of the linear Poisson-Boltzmann equation, and distortion of the ion atmosphere from equilibrium (ion relaxation) ignored (Yoon, B. J.; Kim, S. J. Colloid Interface Sci. 1989, 128, 275). This model provides good agreement with experiment but only if the net absolute protein charge is low or the average absolute surface, or zeta, potential is less than similar to25 mV. Boundary element (BE) modeling is also carried out in which detailed surface models are employed and the electrostatics are solved at the level of the nonlinear Poisson-Boltzmann equation. Ion relaxation is also included in some of the BE studies' All of the experimental mobilities are in good (human carbonic anhydrase II and hen ovalbumin) to excellent (bovine alpha-lactalbumin, hen egg white lysozyme, and bovine superoxide dismutase) agreement with BE modeling that includes ion relaxation. We believe that these results taken as a whole serve to confirm the ability of the continuum primitive model to predict, with quantitative accuracy, the free solution electrophoretic mobilities of proteins, provided the underlying models are sufficiently realistic. When a discrepancy occurs, it may be due to error in modeling either the protein charge or the solution conformation. The mode, Is described in this work also provide a useful approach for determining values of DeltaZ, the change in net charge of proteins due to the chemical modification of charged groups. Knowledge of DeltaZ is essential for the use of protein charge ladders in the quantitative description of the electrostatic properties and interactions of proteins. This paper supports the view that the continuum primitive model may be more appropriate for the modeling of electrokinetics than for electrostatics. The main challenge to the accurate predictions of electrophoretic mobilities may lie primarily in the modeling of electrostatics, not electrokinetics.