High-risk myelodysplastic syndromes (HR-MDS) and acute myeloid leukemia (AML) with deletions of long arm of chromosome 5 (del[5q]) are characterized by rapid progression and poor survival. The majority of these patients are elderly with comorbidities, therefore limiting the use of intensive therapies which, even if used, unfortunately yield low responses. While azacitidine prolongs survival in patients with HR-MDS by a median of 9.5 months, responses only occur in less than half of the patients, and azacitidine therapy is not curative, with most patients relapsing within 2 years. Therefore, strategies to improve outcomes in these patients are needed. Azacitidine and lenalidomide both have meaningful single-agent clinical activity in HR-MDS and AML with del(5q). Early-phase trials in HR-MDS without del(5q) suggest increased activity with a concurrent azacitidine-lenalidomide combination. In this article, we review the results of a Phase I trial of a sequential azacitidine-lenalidomide combination approach in patients with HR-MDS and AML with del(5q) abnormality.