Sickle cell disease (SCD) is the most common severe inherited disorder affecting millions of people. The condition arises from the presence of the abnormal haemoglobin HbS in patients’ red blood cells (RBCs). Deoxygenated HbS can polymerise and the multiple complications of SCD all follow from this. There is no effective therapy although hydroxyurea is given to more severely affected patients. One possible treatment rationale is use of drugs which interact directly with HbS, increasing its oxygen affinity to reduce polymerisation and lessen vascular problems in blood vessels with moderately low oxygen tension. The most successful reagents which act in this way have been the aromatic aldehydes. A number of them reduce sickling but, to date, none has proved clinically useful. The heterocyclic aldehyde 5-hydroxymethyl-2-furfural (5HMF or Aes-103) was identified around a decade ago. 5HMF is certainly effective on sickle RBCs in vitro. It reduces sickling and mortality in transgenic sickle mice and has progressed to phase two clinical trials in humans. Nevertheless, there are potential caveats which argue against it becoming clinically useful. Further data from trials are keenly awaited whilst newer compounds with similar actions continue to be discovered. The best will target RBCs specifically, hence reducing possible side-effects.