Over the past decade, the glycosaminoglycans heparin and heparan sulfate have been shown to bind and regulate the activities of many proteins. Established techniques have provided both qualitative and quantitative information regarding these interactions, leading to a general view that proteins bind with a variety of affinities to particular sequences within heparin or heparan sulfate chains. The mechanism by which heparan sulfate regulates the activity of proteins through such interactions has, however, proved more elusive. We survey some relevant details of the structural characteristics of heparin/heparan sulfate and the approaches used to investigate their interactions with proteins. For the latter, the interactions of heparin/heparan sulfate with fibroblast growth factors and their receptors will be emphasized, because these proteins have been the subject of many studies. We reflect on the information that various techniques have provided, points regarding their use, and some relevant theoretical considerations regarding the study of protein-heparin/heparan sulfate interactions. A perspective of new and developing approaches, which may aid advances in this field, is also provided.