Despite remarkable effort, malignant melanoma still remains a potent killer. Millions of dollars have been spent on clinical trials that have not succeeded in achieving significant patient benefit. The thorough validation of drug targets at an earlier stage is, therefore, an essential step in the development of new therapies. Since the development of microarray experiments, putative drug targets are being identified in a high-throughput manner. Though high-throughput functional validation methods are currently being established, a more specific, pre-clinical analysis of promising target genes remains inevitable. For this, a broad range of increasingly sophisticated functional models is available. In vitro, the microenvironment of skin can be simulated through various two or three-dimensional models. In vivo assays range from xenograft studies to the establishment of transgenic organisms. Here, we provide a summary of functional interrogation approaches in melanoma research, focusing on the application of these strategies to the development of new effective therapies.