Protein glycosylation represents the most abundant extracellular posttranslational modification in multicellular organisms. These glycoproteins unequivocally comprise the major biomolecules involved in extracellular processes, such as growth factors, signaling proteins for cellular communication, enzymes, and proteases for on- and off-site processing. It is now known that altered protein glycosylation is a hallmark event in many different pathologies. Glycoproteins are found mostly in the so-called secretome, which comprises classically and nonclassically secreted proteins and protein fragments that are released from the cell surface through ectodomain shedding. Due to biological complexity and technical difficulty, comparably few studies have taken an in-depth investigation of cellular secretomes using system-wide approaches. The cellular secretomes are considered to be a valuable source of therapeutic targets and novel biomarkers. It is not surprising that many existing biomarkers, including biomarkers for breast, ovarian, prostate, and colorectal cancers are glycoproteins. Focused analysis of secreted glycoproteins could thus provide valuable information for early disease diagnosis, and surveillance. Furthermore, since most secreted proteins are glycosylated and glycosylation predominantly targets secreted proteins, the glycan/sugar moiety itself can be used as a chemical “handle” for the targeted analysis of cellular secretomes, thereby reducing sample complexity and allowing detection of low abundance proteins in proteomic workflows. This review will focus on various glycoprotein enrichment strategies that facilitate proteomics-based technologies for the quantitative analysis of cell secretomes and cell surface proteomes.