Studies in yeast, files and mammalian cells have uncovered a novel family of signal-transducing kinases which bear an evolutionary relationship to phosphatidylinositol 3-kinase. These phosphatidylinositol 3-kinase related enzymes play critical roles in DNA repair, V(D)J recombination and cell-cycle checkpoints, and their dysfunction leads to clinical manifestations ranging from immunodeficiency to cancer.