Molecular modeling provides a mechanistic hypothesis at the molecular level for the constitutive activation recently observed and reported for tyrosine protein kinases Flt-3 and c-Kit. Three-dimensional homology models for the active and inactive forms of these two kinases were made. Comparison of these models at the molecular level reveals that mutations of specific residues located in the activation loop (D835X and 836-deletion in Flt-3; D816V in c-Kit) as well as a 6-base pair (6-bp) insertion at residue 840 in Flt-3 operate in a similar way. Each mutation tends to weaken the forces that maintain the activation-loop folded inwards. None of the mutations are found to particularly stabilize the active state directly. The reason why the equilibrium is shifted towards the gate-open conformation of the protein is because, at least in these models, the mutations are found to critically destabilize the inactive conformational state of the kinase.