Glypican 4 (GPC4), a member of the cell surface heparan sulfate proteoglycan family, plays a crucial role in regulating various cell signaling and developmental processes. Its ability to be released from the cell surface into the bloodstream through shedding makes it a promising blood-based biomarker in health and disease. In this context, circulating GPC4 has been initially proposed as an insulin-sensitizing adipokine being linked with various conditions of insulin resistance. In addition, serum levels of GPC4 can indicate glycocalyx shedding and associated pathophysiological states, such as systemic inflammation. Particularly in a morbid and elderly population, increased GPC4 concentrations may reflect general organ dysfunction and an advanced state of multimorbidity, showing a strong association with the prognosis of severe conditions such as heart failure or advanced cancer. This comprehensive review is the first to summarize the existing scientific knowledge on the role of circulating GPC4 as a novel diagnostic and prognostic biomarker across different pathologic conditions. We also discuss in detail the putative underlying pathophysiological mechanisms behind these findings.