Inclusion Criteria:

• Diagnosis of myelofibrosis requiring therapy, including those previously treated and relapsed or refractory, or if newly diagnosed, with intermediate or high risk according to Lille scoring system (risk factors are: Hb < 10 g/dl, WBC < 4 or > 30 x 109/L; risk group: 0 factor(s) = low, 1 factor(s) = intermediate, 2 factor(s) = high) or with symptomatic splenomegaly
• Understanding and voluntary signing an IRB-approved informed consent form.
• Age >/= 18 years at the time of signing the informed consent.
• Disease-free of prior malignancies for >/= 2-years with exception of basal cell or squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast.
• ECOG performance status 0 to 2.
• Patients must have adequate organ function as demonstrated by the following: Total bilirubin </= 2.0 mg/dL (unless higher due to MF); Serum creatinine </= 2.0 mg/dL (unless higher due to MF); Absolute neutrophil count >/= 1 x 10^9/L; ALT </= 3 x upper limit of normal (unless higher due to MF).
• Females of childbearing potential (FCBP)† must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to and again within 24 hours of starting lenalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 4 weeks before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing.
• Continuation of 7. Men must agree to use a condom during sexual contact with a female of child bearing potential even if they have had a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. See Appendix J: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods
• footnote to no 7. † A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
• All study participants must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist®.

Exclusion Criteria:

• Use of any other standard (e.g. hydroxyurea, anagrelide, growth factors) or experimental drug or therapy within 28 days of starting lenalidomide and/or lack of recovery from all toxicity from previous therapy to grade 1 or better.
• Known prior clinically relevant hypersensitivity reaction to thalidomide, including the development of erythema nodosum if characterized by a desquamating rash.
• Prior therapy with lenalidomide.
• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
• Suspected Pregnancy. Pregnant or lactating females.
• Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.
• Known positive for HIV or infectious hepatitis, type A, B or C.
• Known prior clinically relevant hypersensitivity to prednisone.
• Participants with a heart rate (HR) of less than or equal to 50, as a HR less than 50 indicates underlying cardiac abnormalities.
• Participants with prior history of thromboembolic disease (i.e.-deep venous thrombosis [DVT] or pulmonary embolism [PE]) within the last six months, as Lenalidomide has demonstrated a significantly increased risk of DVT or PE.