The secretome includes all macromolecules secreted by cells, in particular conditions at defined times, allowing cell-cell communication. Cancer cell secretomes that are altered compared to normal cells have shown significant potential for elucidating cancer biology. Proteins of secretomes are secreted by various secretory pathways and can be studied using different methods. Cancer secretomes seem to play an important role in known hallmarks of cancers such as excessive proliferation, reduced apoptosis, immune invasion, angioneogenesis, alteration in energy metabolism, and development of resistance against anti-cancer therapy [1, 2]. If a significant role of an altered secretome can be identified in cancer cells, using advanced mass spectrometry-based techniques, this may allow researchers to screen and characterize the secretome proteins involved in cancer progression and open up new opportunities to develop new therapies. We aim to elaborate upon recent advances in cancer cell secretome analysis using different proteomics techniques. In this review, we highlight the role of the altered secretome in contributing to already recognized and emerging hallmarks of cancer and we discuss new challenges in the field of secretome analysis.