Myelodysplastic syndrome (MDS) is a hematopoietic stem cell disorder primarily affecting CD34+ cells, characterized by ineffective hematopoiesis, often transforming into acute myelogenous leukemia (AML). A subset of patients has 5q deletion (del(5q)) as the culprit pathogenetic trigger. Del(5q) affects critical regions 5q31 and 5q33, leading to gene haplodeficiency with subsequent RPS14 haplodeficiency and P53 activation. Subsequent to P53 activation, erythroid cell apoptosis and ineffective erythropoiesis occur. Other pathogenetic elements include protein phosphatase 2a and CDC25C haplodeficiency and decreased miR-145 and miR-146a expression. Lenalidomide is an immunomodulatory agent that selectively suppresses the del(5q) clone. While the mechanism is not fully understood, it is associated with diverse molecular changes including stabilization of MDM2 with subsequent enhanced P53 degradation. Lenalidomide showed success in low- and intermediate-1-risk MDS as reported in the 002, 003, and 004 trials. However, in higher-risk MDS, the results of lenalidomide monotherapy were modest, mandating the use of combination therapy. The role and priority of lenalidomide varies between different guidelines, and accordingly, future efforts are necessary to reach a unified therapeutic algorithm. TP53 mutations are important predictors of AML progression and possible resistance to lenalidomide. It is recommended to identify TP53 mutation early in the disease since it may change the decision regarding choice of therapy. Challenges with lenalidomide therapy remain the long-term effects and timing of its discontinuation.