Ion-specific effects underlie a vast array of physicochemical and biological phenomena ranging from human physiology to biotechnology to ecology. These effects have traditionally been quantified by measuring the response of interest in a series of salt solutions at multiple concentrations; pH has consistently been shown to be of primary concern. However, salt-based approaches violate critical tenets of proper experimental design and introduce confounding errors that make it impossible to quantify ion-specific effects. For example, pH is a variable dependent on the type and concentration of ions in a solution, but is typically treated as an independent factor, thus confounding experiments designed to determine ion-specific effects. We examined the relevancy of ion-specific effects research in relation to these concepts and demonstrated how these ideas impact protein precipitation and enzyme activity. Based on these results, we present a conceptual and experimental framework of general applicability for proper quantification of ion-specific effects.