Dry mouth, also known as xerostomia, is a condition in which insufficient or ineffective saliva does not provide sufficient oral lubrication. The severity of this condition can vary from a mild discomfort to a debilitating condition that greatly impairs patients’ lives. Xerostomia arises as a side effect of various medications, diseases, radiation therapy, chemotherapy, or nerve damage. Various aqueous dispersions of macromolecules have been proposed to assist or replace the saliva in these patients. It is vital that these macromolecules have ample lubricity and water retention properties while showing long-lasting efficacy. The emphasis of this review is to provide a general overview on lubricating macromolecules that have been clinically used or reported in the literature as potential replacements for saliva. These include various natural or synthetic polymers, proteins, peptides, and lipids that are used in the form of solutions, gels, emulsions, and colloids. Perspectives into the future of macromolecular oral lubricants in the treatment of xerostomia are also provided.