Inclusion Criteria:

• Patients must have either: 1) histologically or cytologically confirmed hepatocellular carcinoma, or 2) serum alpha fetoprotein greater than 1000 ng/dL with characteristic imaging findings coupled with the appropriate clinical scenario (chronic hepatitis and/or cirrhosis). Eligible patients must either have metastatic disease (including any proven lymph node metastases) or localized disease not amenable to potentially curative transplant/locoregional/surgical therapy as determined by a qualified surgeon or tumor board. Questions regarding suitability of an individual patient for study may be directed to the PI given the inability of standard TNM staging to direct the appropriate treatment strategy for HCC.
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm with conventional techniques or as >10 mm with spiral CT scan. See Section 11 for the evaluation of measurable disease.
• Prior therapy: No prior systemic chemotherapy, sorafenib, therapeutic antibody or experimental systemic therapy (oral or intravenous) is allowed. No prior hepatic artery infusion of chemotherapy is allowed. Prior chemoembolization, radioembolization (90Y microspheres), or radiofrequency/cryo- ablation is permitted. Patient must be at least 4 weeks from time of embolization, resection, or ablation, and must have either measurable disease outside the treated area or unequivocal evidence of disease progression within the treated area to be eligible. Patients must be more than 4 weeks out from any radiotherapy or major surgery. Patients post-liver transplantation are ineligible.
• Age >= 18 years.
• Life expectancy of greater than 3 months.
• ECOG performance status ≤ 2.
• Patients must meet the following limits on organ and marrow function: leukocytes >=3,000/mcL; absolute neutrophil count >=1,500/mcL; platelets >=75,000/mcL; total bilirubin Less than 2X ULN; AST(SGOT)/ALT(SGPT) <5 X institutional ULN; creatinine <1.5 mg/dL OR creatinine clearance >60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal; INR < 1.4
• If cirrhosis is present, must be Child's A or B cirrhosis. If Child's B cirrhosis is present, the patient cannot have significant encephalopathy or ascites that requires paracentesis and must meet above laboratory criteria (i.e. well-compensated Child's B).
• The effects of AZD6244 on the developing human fetus at the recommended therapeutic dose are unknown. For this reason women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for four weeks after dosing with AZD6244 ceases. Women of child-bearing potential must have a negative pregnancy test prior to entry. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Please note that the AZD6244 manufacturer recommends that adequate contraception for male patients should be used for 16 weeks post-last dose due to sperm life cycle.
• Ability to understand and the willingness to sign a written informed consent document.
• Willingness to undergo protocol-required tumor biopsies. Must also be able to have any anticoagulation held for an appropriate period of time, and meet above criteria for platelet count and prothrombin time.

Exclusion Criteria:

• Patients who have not recovered from adverse events due to agents administered more than 4 weeks earlier (e.g. embolization).
• Patients may not be receiving any other investigational agents.
• Patients with known brain metastases are excluded regardless of prior treatment.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD6244 or its excipient Captisol®.
• Previous MEK inhibitor use.
• Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g. inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant women are excluded from this study because the effects of AZD6244 on the developing human fetus at the recommended therapeutic dose are unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother, breastfeeding should be discontinued if the mother is treated with AZD6244.
• HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD6244. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
• Active illicit substance or alcohol abuse.
• Prior organ transplant is an exclusion.