Introduction

Melanoma is the deadliest of skin cancers and improved treatment strategies are desperately needed as standard treatments for metastatic disease offer response rates of only 15–20%. The American Cancer Society predicted 76250 new cases of melanoma in the United States alone and 9680 deaths for 2012, despite avid efforts in prevention, diagnosis, and advanced treatments (1). However, significant strides are continuously being made in our understanding of the disease, which, combined with a flourishing library of novel small-molecule inhibitors, keep us poised for improved treatment outcomes.

Melanoma is caused by the transformation of melanocytes which have accumulated genetic alterations leading to abnormal proliferation and dissemination. Predisposition to the disease can be influenced by individuals’ genetic background, pigmentation status, and exposure to ultraviolet light (UV; 2). Clinically, melanoma lesions can be classified into five groups based on location and progression: common acquired and congenital nevi without dysplastic changes; dysplastic nevi with structural and architectural atypia; radial growth-phase melanoma (RGP); vertical growth phase melanoma (VGP) in situ or invasive through the dermis; and metastatic melanoma (2,3). Meanwhile, tumor-node-metastases (TNM) staging focuses on melanoma thickness and ulceration (T category), number of metastatic lymph nodes and tumor burden in each node (N category), and visceral or non-visceral metastases (4). Unfortunately, current classifications do not always predict survival or response to therapy (5). This is not surprising given that the histomorphologic classification of melanoma hardly reflects the complex and heterogeneous genetic and molecular processes driving the disease. Efforts to integrate such knowledge is underway (6), and novel genotype–phenotype relationships are expected to emerge and reform current classification systems. The following chapter briefly summarizes the important mutations, signal transduction pathways, and therapeutic endeavors associated with melanoma, the integration of which has begun and has already shown therapeutic promise.