Cancer is a leading cause of death world wide and mortality due to this group of diseases has doubled in the last 20 years. With an estimated 3 million cases, skin cancer is currently the third most common human malignancy and global incidence is rising at an alarming rate due to environmental changes. Within that category, melanomas represent the least common, but most dangerous form accounting for the majority of skin cancer-related deaths. In general terms, cancer evolves as the consequence of a multi-factorial process that involves the loss of a cell’s ability to respond in an appropriate fashion to cues provided by the microenvironment. The development of such aberrant, autonomous behavior is caused by both genetic mutations and epigenetic mechanisms. Particularly relevant in the context of melanoma are the Ras/Raf/MEK/Erk, PI3K/PTEN and NF-kB signaling pathways. The Wnt/┚-catenin patway is also implicated, but it s role still remains unclear. Depending on whether changes result in a “gain of function” or a “loss of function”, the molecules involved are classified as either oncogenes or tumor suppressors, examples important in melanomas being NRas and B-Raf or PTEN, respectively. More recently, a new group of molecular participants has begun to emerge, which, depending on the cellular context, display the ability to either block tumor development or favor progression. Very little is still known about the underlying mechanisms that might explain such “ambiguous” behavior. In this respect, work from our laboratory has focused on the study of a scaffolding protein called caveolin-1. This protein is implicated in a large number of cellular processes, including caveolae formation and vesicular transport, cholesterol transport and the regulation of signal transduction. With respect to tumor development, initial reports implicated caveolin-1 as a tumor suppressor. For instance, caveolin-1 expression is reduced in several human tumors including lung, mammary, colon, ovarian carcinoma and sarcomas, as wells as osteosarcomas and re-expression of the protein can reverse characteristics associated with the transformed phenotype. However, evidence to the contrary is also available showing that caveolin-1 promotes more aggressive traits in tumor cells, such as metastasis and multidrug resistance. Importantly, in human melanoma patients high levels of caveolin-1 are detected in exosomes found in the plasma and some data available associate caveolin-1 expression with increased metastatic potential in different human melanoma cell lines. In this chapter, we summarize data available in the literature highlighting the ambiguity of caveolin-1 function in cancer development. Mechanisms that might explain one or the other