PARP inhibitors for the treatment of BRCA, PALB2 and other HRD-associated tumors, immune checkpoint inhibitors for the dMMR tumors that include Lynch Syndrome-related cancers, HIF-2α inhibitors in the VHL-related cancers, selective RET inhibitors for the treatment of MEN2-associated medullary thyroid cancers and finally, Hedgehog pathway inhibitors in basal cell nevus syndromes are the most successful examples of how germline PVs can be exploited to develop effective personalized therapies and improve the outcome of these patients. This evidence concerns the gene EPAS1 and nevoid basal cell carcinoma syndrome.