Communication between cells of the immune system and the organism is dependent on information processing mediated by proteins of the cell surface. The cell surface proteome consists of a group of functionally diverse proteins, which not only enables but also limits the interaction capacities of cells within their particular microenvironment. Although these proteins represent a highly important proteome for immunological research, most routinely used technologies for their detection only allow for a fragmented view of the ensemble of cell surface located proteins. A major bottleneck is the limited availability of high quality antibodies against cell surface protein targets that altogether impedes a Systems Biology view on the cell surface proteome (surfaceome) and its concerted functions during signal processing. Recent developments in mass spectrometry-based technologies enable now complementary approaches for the qualitative and quantitative analysis of the surfaceome. Here, we highlight recent progress in the field towards the identification and quantification of the surfaceome as an important subproteome forming the information gateway of the cell.