Parenteral nutrition (PN) provides a means of nourishment for patients in whom oral or enteral nutrition is not possible or practical. Initial formulations consisted of carbohydrates (dextrose), amino acids, vitamins, trace minerals, electrolytes, and water. A stable intravenous fat emulsion (IVFE) permitted the combination of all 3 macronutrients in the same admixture (3-in-1 or total nutrient admixture [TNA]). Many institutions have adopted these TNAs as the standard formulation. Others, due to a variety of concerns (including historical concerns regarding stability), continue to administer PN as a formulation of dextrose and amino acids (2-in-1) with separate IVFE infusions. The aim of this article is to review the literature regarding the use of TNA vs 2-in-1 formulations. The published data were critically analyzed, and a preferred strategy was suggested based on an interpretation of the data. Concerns surrounding the safety of 2-in-1 vs 3-in-1 PN formulations can be grouped with respect to those regarding infections, emulsion instability (“cracking”), and precipitant formation. These concerns are largely historical and would seem to be no longer relevant to adult PN formulations. We believe that the available (limited) data support the safe transition to the 3-in-1 formulation as the standard of care in adult PN. (Nutr Clin Pract. 2014;29:631-635)