Hydroxyurea and multi-agent therapy. Although hydroxyurea (HU) has been used for decades in a variety of diseases, and its overall safety is well documented, there are still some unresolved questions regarding its long-term use. Guidelines continue to advise against HU when male or female patients plan to conceive a child, and questions remain about the effect of HU on spermatogenesis^77,78  and ovarian reserve. In industrialized countries, management of HU treatment most often involves titration to maximum tolerated dose (MTD), but recent studies in Africa have documented the feasibility and benefit of fixed dosing without such resource-intensive monitoring.^70,73,75  Concerns also persist regarding the possibility that long-term HU therapy reduces the number and viability of pluripotent stem cells and may predispose to myelodysplasia.⁷²  The efficacy of HU in preventing organ damage, such as cardiac dysfunction, also remains uncertain. Now, to improve overall SCD therapy, we need to learn how to prescribe HU in combination with other, differently targeted therapies, such as those already FDA approved. Hopefully, additional therapies with additive or different therapeutic effects will be added to this list in the future. ACS, acute chest syndrome; MDS, myelodysplastic syndrome.