Germ-line mutations in specific genes predispose family members to cancer. Prediction of the exact tumor type and timing of cancer initiation is fundamental to the development of management strategies for these individuals. Recent advances in our understanding of the general processes that control cancer initiation may enable us to tailor more precise risk stratification. This, in turn, will lead to more effective early detection strategies, which would result in more favorable clinical outcomes. In this review, we highlight the steps and methods used to reach this futuristic model.