Most cellular processes occur in systems containing a variety of components, many of which are open to material exchange. However, computer simulations of biological systems are almost exclusively performed in systems closed to material exchange. In principle, the behavior of biomolecules in open and closed systems will be different. Here, we provide a rigorous framework for the analysis of experimental and simulation data concerning open and closed multicomponent systems using the Kirkwood–Buff (KB) theory of solutions. The results are illustrated using computer simulations for various concentrations of the solutes Gly, Gly₂, and Gly₃ in both open and closed systems, and in the absence or presence of NaCl as a cosolvent. In addition, KB theory is used to help rationalize the aggregation properties of the solutes. Here, one observes that the picture of solute association described by the KB integrals, which are directly related to the solution thermodynamics, and that provided by more physical clustering approaches are different. It is argued that the combination of KB theory and simulation data provides a simple and powerful tool for the analysis of complex multicomponent open and closed systems.