Although cellular environment represents a kind of pottage with the increased viscosity and molecular interactions, changed water activity, volume exclusion, and considerably restricted amounts of free water, most of the biomolecular research in vitro is traditionally conducted under the “physiological conditions”; i.e., in warm, slightly salted, neutral or slightly alkaline aqueous solution, where the effects of such crowded environment on the behavior of biological macromolecules are mostly ignored. Furthermore, macromolecular crowding is spatially and temporally heterogeneous, as cell contains numerous biological condensates, overcrowded liquid droplets, which, being formed in response to the changing environment, reflect complexity of the cellular molecular kitchen. This chapter represents a brief historical overview of the developments in the field of macromolecular crowding reflecting the evolution of understanding of what are the appropriate experimental conditions for gaining the most accurate information on the behavior of biological macromolecule in biological systems.