Discusses the sickling of red blood cells from a biophysical-chemical view, and develops a rationale for a screening methodology to be used in selecting therapeutic agents for alleviating the symptoms of sickle-cell crises. Low solubility of deoxygenated hemoglobin S (HbS) is accepted as the ultimate cause of the signs and symptoms of sickle-cell disease and associated crises. The study surveys methods that may increase solubility of HbS. They involve, in one manner or another, the physicochemical solution properties of the blood fluids, and include: salting-in of HbS; altering the relative activity coefficients for water in plasma and erythrocytes; and increasing presickling cell volumes through osmosis, inhibited cell metabolism, and controlled hemolysis. The study lists and discusses possible therapeutic agents that each of these modes suggests as possible candidates for evaluation.