The availability of the Platelia Aspergillus, a sandwich ELISA kit that detects circulating galactomannan, has been a major advance for managing patients at risk for invasive aspergillosis because of the early detection of the antigen. The assay is now widely used throughout the world, including the USA. Although initial studies that assessed the performance characteristics of this assay reported high sensitivity and specificity, more recent studies show significant variation in performance. The causes of this variability are multifactorial and, in large part, cannot be explained because there is insufficient understanding of the kinetics of galactomannan in vivo. We explored some of the factors that affect the release of the aspergillus antigen that bears the epitope that reacts with the monoclonal antibody used in the ELISA, its leakage from the site of infection into the blood, and its binding to substances present in the blood. Factors that affect the detection of antigen in blood are also discussed, most notably the pretreatment procedure aimed at liberating the antigen from immune complexes. Understanding the biology of galactomannan release by aspergillus will greatly enhance our understanding of the kinetics of this and other surrogate markers and allow their optimum use in the management of invasive aspergillosis.