The goal of this study was to better understand the possibilities and limitations of modern cation exchange chromatography (CEX) columns for the separation of protein biopharmaceuticals (typically mAbs and related products). Several commercial and research columns consisting of a non-porous polymeric core particle with a thin hydrophilic coating and grafted ion-exchanger sulfonate groups, were compared. The impact of particle size, porosity and packing pressure on the separation of therapeutic proteins was evaluated in a systematic way. First, it was shown that the porosity of modern CEX columns depends on the applied conditions, and lower apparent porosity as well as increased column pressures were observed when using low ionic strength mobile phase (less than 0.01 M NaCl), due to swelling. Column pressure seemed to be dependent on the 1/dp3 to 1/dp5 relationships with particle size, depending on whether 0.3 M NaCl or pure water was used as mobile phase, respectively. Using 5 cm long columns packed with 2 or 2.5 µm particles could easily result in higher than 1000 bar pressure drops when the mobile phase ionic strength is low. Therefore, it is recommended that particle size not be decreased to below 2.5 µm so that technologies can remain compatible with the current state of ultra-high pressure (UHPLC) instrumentation. This recommendation is underscored by the fact that a decrease in particle size does not produce improved separations, since the particles are non-porous (no intra-particle diffusion nor resistance to mass transfer) and that large solutes follow an on-off (bind and elute) type retention mechanism. The only advantage of CEX columns packed with small particles is that they can provide more specific surface area per unit length of column, and thus facilitate higher throughput methods. In conclusion, it appears that there is no need to further decrease the particle size in CEX since decreasing their particle size may result in more drawbacks than benefits.