With the availability of these noninvasive imaging modalities, one can now obtain more objective information about microcirculatory pathophysiology. As a result, previously held pathophysiologic paradigms in sickle cell disease will undoubtedly require modification or abandonment. These approaches should be viewed as supplements, not substitutes, for more traditional evaluations. Nonetheless, since these techniques are amenable to sequential application, these approaches promise to define disease severity more precisely, in quantitative terms, and should provide the means to follow the results of therapy unambiguously.