In-situ tissue engineering (TE) of valves and vessels has rapidly progressed over the past two decades as it prospects a great alternative to autologous, xenografted, and non-biological materials for valve and vessel replacements. In this approach a degradable synthetic valve replacement is implanted at the site of a diseased, degenerated, or malformed valve or vessel, where it gradually remodels into a viable, living tissue. To date, however, some outstanding challenges prevent a safe clinical translation of this approach, one of them being the formation of calcification nodules within the grafts. Calcification formation is commonly found in preclinical evaluations of in-situ tissue engineered scaffolds remodeling in vivo. Yet, the exact causes of calcification in these materials, relevant to prevent this drawback, are unknown. In this study we aim to unravel the driving mechanisms of calcification within in-situ tissue engineered constructs, with the goal to prevent calcification in these constructs. We will combine knowledge from the fields of biological bone mineralization and in-vivo pathological calcification of valves and vessels with data from calcification in in-situ tissue engineered constructs obtained from explanted grafts from previous in vivo studies, as well as data from dedicated in vitro and in vivo experiments. We aim to answer what is happening when in-situ tissue engineered scaffolds calcify and why this happens. Answering these questions can finally teach us how we can prevent calcification of in-situ tissue engineered valves and vessels.