Advanced melanoma has the highest per-death loss of years of potential life expectancy second only to adult leukemia. The incidence of melanoma continues to rise worldwide at approximately 3% per year, and in 2009 there were an estimated 68,720 new cases in the United States and 8650 deaths (Balch et al. 2009). According to Surveillance Epidemiology and End Results (SEER) data, roughly 4% of melanomas are metastatic at time of diagnosis. Locally advanced or recurrent unresectable, and disseminated melanoma is notoriously unresponsive to standard treatment, and is associated with a dismal prognosis. Patients with metastatic melanoma have a median survival of 8 months and 2-year survival rates of 10% to 15%. (Tsao et al. 2004). Until March of 2011, only 2 drugs were approved by the Food and Drug Administration (FDA) in the United States (US) for metastatic melanoma: interleukin 2 (IL-2) and dacarbazine (ipilimumab was approved in March of 2011 and will be discussed in this chapter). Dacarbazine is an alkalyting agent that in 1975 became the first chemotherapeutic drug approved by the US FDA for metastatic melanoma. Response rates for this regimen were 20% in a 30-year overview (Serrone et al. 2000), whereas more recent studies showed response rates in the 10-14% range (Bedikian et al. 2006; Chapman et al. 1999; Middleton et al. 2000). Temozolomide, an orally available congener of dacarbazine, was shown to be non-inferior in efficacy in comparison to dacarbazine in a randomized phase III trial (Middleton et al. 2000). Temozolomide had a similar objective response rate and overall survival compared to dacarbazine, and a significantly longer disease free survival. IL-2 was approved by the US FDA in 1998 for the treatment of metastatic melanoma. Single agent IL-2, when given in high dose intravenous boluses, leads to objective responses in 16% of patients, with complete responses in 6% and partial responses in 10%. Many patients maintained a complete response even after 7 years follow-up (Atkins et al. 2000). The toxicities of high dose IL-2 are substantial, including constitutional symptoms (fevers, chills, fatigue), hypotension, renal insufficiency, emesis, diarrhea and thrombocytopenia, and up to 2% of mortality is directly related to the treatment (Atkins et al. 2000). A systemic review of 41 randomized clinical trials including patients receiving various treatment schedules including biochemotherapy did not show improved progression-free survival (PFS) or overall survival (OS) (Eigentler et al. 2003). More recently, another meta-analysis of 18 trials involving nearly 2,500 patients with metastatic melanoma suggested an increase in response rate to biochemotherapy, but overall survival was not improved (Ives et al. 2007). Until today, biochemotherapy and combination chemotherapy built upon IL-2 and dacarbazine or temozolomide has not shown statistically