YKL-40 is a 40 kDa glycoprotein produced by cancer cells, inflammatory cells and stem cells. It probably has a role in cell proliferation and differentiation, inflammation, protection against apoptosis, stimulation of angiogenesis, and regulation of extracellular tissue remodelling. Plasma levels of YKL-40 are often elevated in patients with localized or advanced cancer compared to age-matched healthy subjects. Several studies have demonstrated that high plasma YKL-40 is an independent prognostic biomarker of short survival in patients with different types of cancer. However, there is not yet sufficient data to support determination of plasma YKL-40 outside research projects as a biomarker for screening of gastrointestinal cancer and determination of treatment response and poor prognosis before or during treatment and follow-up. Plasma YKL-40 is also elevated in patients with other diseases than cancer, e.g., severe infections, cardiovascular disease, diabetes, chronic obstructive lung disease, asthma, liver fibrosis and rheumatoid arthritis. Co-morbidity should therefore always be considered in patients with cancer, since other sources than cancer cells can increase plasma YKL-40 levels. Future focused translational research projects combining basic and clinical research are needed in a joint effort to answer questions of the complex function and regulation of YKL-40 and the question if plasma YKL-40 is a clinical useful biomarker in patients with cancer.