The elimination of product and process related impurities is essential to the safety and efficacy of biopharmaceuticals. To achieve this goal, multiple separation steps are often required at the expense of target yield. We have recently developed a new mixed-mode chromatography media, Nuvia aPrime 4A, with a positively charged hydrophobic functional ligand. We will illustrate the possible orthogonal interactions between the Nuvia aPrime 4A ligand and the incoming biomolecules, and the rational design of chromatography conditions. Nuvia aPrime 4A can be operated in flow-through as well as bind-and-elute modes under gentle conditions. We will demonstrate case study examples using protein molecules with acidic or basic isoelectric point (pI) to showcase the advantages of using this new chromatography media to address protein purification challenges. Our data indicate that Nuvia aPrime 4A is more efficient in clearing a wide variety of contaminants from expression host cells than the traditional ion exchange chromatography resins.