In vitro modeling of complex diseases is now a possibility with the use of patient-derived induced pluripotent stem (iPS) cells. Their stem cell properties, including self-renewal and their potential to virtually differentiate into any cell type, emphasize their importance as a translational tool for modeling disorders that so far have been limited by the unavailability of primary cell lines, animal models, or inaccessible human materials. Around 100 genes with germline mutations have been described to be responsible for cancer predisposition. Familial cancers are usually diagnosed earlier in life since these patients already carry the first transforming hit. Deriving iPS cells from patients suffering from familial cancers provides a valuable tool for understanding the mechanisms underlying pediatric cancer onset and progression since they require less mutation recurrence than adult cancers to develop. At the same time, some familial mutations are found in sporadic cases and are a valuable prognostic tool. Patient-derived iPS cells from germline malignancies can also create new tools in developing specific drugs with more personalized-therapy strategies.