The structural synergy between biominerals (CaCO3, hydroxyapatite) and biosubstrates were examined for the first time. The templating effect of substrate and a newly identified supersaturation-driven interfacial structure mismatch effect were identified in the context of a new nucleation model. It follows that the heterogeneous nucleation which corresponds to a good structural match and synergy between biominerals and substrates will promote an ordered, compact, and tough complex biomineral structure, and occur only at low supersaturations, whereas at high supersaturations the heterogeneous nucleation associated with a poor structural match and synergy between biominerals and substrates will become dominant due to supersaturation-driven interfacial structural mismatch. The latter normally results in a disordered and porous structure. A phenomenon, so-called microgravity-driven homogeneous nucleation, was also examined. It turns out that microgravity will suppress convection and consequently promote homogeneous-like nucleation during biomineralization. This could be responsible for microgravity-induced osteoporousis.