Twenty years ago, a number of eminent pharmaceutical scientists collaborated on an article describing a rational approach to developing stable lyophilized protein formulations (Carpenter, Pikal, Chang, & Randolph, 1997). Since that time, no corresponding document for rational development of liquid formulations of proteins has appeared. Certainly, many of the principles underpinning rational protein formulation have been known for some time, but no overarching scheme has ever been described in the literature. Now the time has come to provide a framework for the rational design of protein formulations as aqueous solutions. The objective of this review is to lay out four concepts that will guide one to obtaining a stable liquid protein formulation. Additionally, the aim will be to identify factors that are intrinsic to the stabilization of any protein, not just a particular class of proteins, such as monoclonal antibodies (Uchiyama, 2014; Wang, Singh, Zeng, King, & Nema, 2007) and to provide guidelines aiming to effect stabilization. Noting that all approaches to stabilization face validation that must be performed empirically, it is hoped that the rational strategies described here will help the formulation scientist in their daily tasks and inspire continued advancement of the science involved in protein formulation.