Glycosaminoglycans (GAGs) are an important component of the tumor microenvironment (TME). GAGs can interact with a variety of binding partners and thereby influence cancer progression on multiple levels. GAGs can modulate growth factor and chemokine signaling, invasion and metastasis formation. Moreover, GAGs are able to change the physical property of the extracellular matrix (ECM). Abnormalities in GAG abundance and structure (e.g., sulfation patterns and molecular weight) are found across various cancer types and show biomarker potential. Targeting GAGs, as well as the usage of GAGs and their mimetics, are promising approaches to interfere with cancer progression. In addition, GAGs can be used as drug and cytokine carriers to induce an anti-tumor response. In this review, we summarize the role of GAGs in cancer and the potential use of GAGs and GAG derivatives to target cancer.