Abstract Melanoma is the deadliest cutaneous malignancy and its incidence continues to grow. Until 2011, the treat- ment options for metastatic melanoma were scarce and without any overall survival benefit. The emergence of new targeted therapies for BRAF mutant melanoma (vemu- rafenib) and immunotherapy (ipilimumab) has changed the standard of care for this disease. The objective of the present review is to summarise the biological background of the new therapeutic approaches in melanoma, focusing on apoptosis resistance, immune modulation and angiogen- esis, and the direct translation into clinical practice. Keywords Melanoma · Apoptosis · Immune system · Vemurafenib · Ipilimumab Introduction Melanoma is still the deadliest skin malignancy. Its in- cidence has increased in the past two decades more than any other tumour, being the second ranked cancer after leukaemia in loss of years of potential life [1–3]. Although it is potentially curable if detected and removed at an early stage, it has a very poor prognosis when it presents as metastatic disease [3, 4]. For many years, the options for these patients were very scarce, dacarbazine (DTIC) (for metastatic) [5] and interferon (for high risk-recurrence melanoma) [6] being practically the only choice of drugs. However, neither of these has demonstrated prolonged overall survival. Moreover, until 2011, no drug alone or in combination had demonstrated superiority in terms of overall survival over DTIC in phase III clinical trials in metastatic melanoma. Fortunately, after years of research in the fields of mo- lecular biology and immunology of melanoma, this land- scape has changed. The emergence of recently approved by FDA ipilimumab and vemurafenib (for BRAF mutated melanoma) brings a new standard of care, since both drugs have improved overall survival in phase III clinical trials. The aim of the present work is to summarise the molecular and clinical key points to understand this cornerstone in the treatment of melanoma and its impact in clinical practice. Melanoma strengths: biological background To understand why efforts in melanoma treatment have failed for more than 30 years, we will briefly explain how this tumour combines aggressiveness and resistance to therapy. The three crucial mechanisms are apoptosis resis- *Supported by an unrestricted educational grant from MSD Oncology I. Márquez-Rodas () · S. Custodio Cabello · M. Martín Servicio de Oncología Médica Hospital General Universitario Gregorio Marañón Universidad Complutense C/ Maiquez, 7 ES-28007 Madrid, Spain e-mail: ivanpantic@hotmail.com S. Martín Algarra Servicio de Oncología Médica Clínica Universidad de Navarra Pamplona, Navarra, Spain J.A. Avilés Izquierdo Servicio de Dermatología Hospital General Universitario Gregorio Marañón Universidad Complutense Madrid, Spain Clin Transl Oncol (2011) 13:787-792 DOI 1007/s12094-011-0734-6 EDUCATIONAL SERIES Yellow Series* A new era in the treatment of melanoma: from biology to clinical practice Iván Márquez-Rodas · Salvador Martín Algarra · José Antonio Avilés Izquierdo · Sara Custodio Cabello · Miguel Martín Received: 12 September 2011 / Accepted: 15 October 2011 ADVANCES IN CLINICAL MANAGEMENT AND THERAPY OF CANCER