Macromolecular crowding affects many areas, including protein folding, binding of small molecules, enzymatic activity, interaction with nucleic acids, protein aggregation, and protein-protein interactions. While the common belief has been that the primary impact of crowded environments on the function, structure, thermodynamics, and aggregation of a protein can be described in terms of excluded volume effects, it has now become clear that other factors, which originate from high concentrations of “inert” macromolecules in crowded solution, must be considered in order to get a clearer understanding a protein’s behavior in a crowded environment. This review will highlight several important factors that arise in a crowded environment, including perturbed diffusion, viscosity, soft interactions, direct physical interactions between the crowding agents and proteins, and, most importantly, the effects of crowders on solvent properties.