“Secretome” is referred to as the rich, complex set of molecules secreted from living cells. In a less strict definition frequently followed in “secretome” studies, the term also includes molecules shed from the surface of living cells. Proteins of secretome (will be referred to as secreted) play a key role in cell signaling, communication and migration. The need for developing more effective cancer biomarkers and therapeutic modalities has led to the study of cancer cell secretome as a means to identify and characterize diagnostic and prognostic markers and potential drug and therapeutic targets. Significant technological advances in the field of proteomics during the last two decades have greatly facilitated research towards this direction. Nevertheless, secretome analysis still faces some difficulties mainly related to sample collection and preparation. The goal of this article is to provide an overview of the main findings from the analysis of cancer cell secretome. Specifically, we focus on the presentation of main methodological approaches that have been developed for the study of secreted proteins and the results thereof from the analysis of secretome in different types of malignancies; special emphasis is given on correlation of findings with protein expression in body fluids.