Vasocclusive events in the sickle-cell syndromes have multiple determinants: first and foremost is the capacity of red cells to undergo intracellular polymerization of deoxy HbS. However, the impact of the sicklable red cell is not limited to mechanical obstruction of the microcirculation, but also results in other and sometimes unexpected consequences. For example, red-cell destruction leads to large numbers of young red cells with enhanced vascular adhesion and increased K:Cl cotransport expression, in addition to an elevated percent of erythrocytic HbF. These pleiotropic effects, that is, multiple phenotypic effects from a single gene, can be further modulated by the action of epistatic effects, that is, the action of other genes besides beta(S). The interaction of epistatic and pleiotropic effects leads to the interindividual phenotypic variations characteristic of sickle-cell disease. Further understanding of pleiotropic effects (i.e. mechanism of red-cell adhesion, production of vasoactive substances by damaged endothelium, etc.), will uncover new epistatic effects. At the end, we will be able to define not only the genotype, but also the phenotypic severity. This review covers the present knowledge of the red-cell and non-red-cell determinants of vasocclusion, and proposes models to explain the acute painful crises that commonly afflict these patients.