The selection of drug candidates with improved pharmacokinetics is essential to reduce the attrition rates during drug development and represents one of the big challenges faced by the pharmaceutical industry. Plasma protein binding (PPB) is an important parameter with significant implications for in vivo drug performance. Today, the most widely used techniques for PPB measurement in the pharmaceutical community are equilibrium dialysis (ED) and ultrafiltration (UF). However, these techniques have some limitations. Thus, we emphasize an alternative strategy, based on a global, new and easy-to-follow methodology, to screen and perform determination of PPB, using orthogonal techniques (i.e. liquid chromatography (LC), capillary electrophoresis (CE), surface plasmon resonance (SPR) based biosensor). We anticipate that the increased knowledge gained through this strategy will lead to improved drug candidates.