Lenalidomide is an immunomodulator used to treat 5q-myelodysplastic syndrome, myelofibrosis, and multiple myeloma. We describe a 55-year-old male who was started on lenalidomide 10 mg daily for 21 days followed by 7 days off therapy for the treatment of early stage post-polycythemia vera myelofibrosis. Following initiation of lenalidomide, the patient was noted to have an asymptomatic increase in unconjugated bilirubin. Alkaline phosphatase, aspartate transaminase, and alanine aminotransferase were normal. During the 7 days off of lenalidomide, bilirubin began to trend down. Re-challenge with lenalidomide in subsequent cycles results in an asymptomatic elevation in unconjugated bilirubin followed by improvement during the 7-day lenalidomide-free period. The patient is a heterozygote for the TA7 allele which can decrease expression of uridine diphosphate glycuronosyl transferase 1A1, the enzyme responsible for conjugation of bilirubin. Therapy with lenalidomide may have unmasked Gilbert's syndrome in the patient.