The DNA‐dependent protein kinase (DNA‐PK) is a trimeric factor originally identified as an enzyme that becomes activated upon incubation with DNA. Genetic defects in either the catalytic subunit (DNA‐PK_CS) or the two Ku components of DNA‐PK result in immunodeficiency, radiosensitivity, and premature aging. This combined phenotype is generally attributed to the requirement for DNA‐PK in the repair of DNA double strand breaks during various biological processes. However, recent studies revealed that DNA‐PK_CS, a member of the growing family of phosphatidyl‐inositol 3‐kinases, participates in signal transduction cascades related to apoptotic cell death, telomere maintenance and other pathways of genome surveillance. These manifold functions of DNA‐PK_CS have been associated with an increasing number of protein interaction partners and phosphorylation targets. Here we review the DNA binding properties of DNA‐PK_CS and highlight its ability to interact with an astounding diversity of nucleic acid substrates. This survey indicates that the large catalytic subunit of DNA‐PK functions as a sensor of not only broken DNA molecules, but of a wider spectrum of aberrant, unusual, or specialized structures that interrupt the standard double helical conformation of DNA.—Dip, R., Naegeli, H. More than just strand breaks: the recognition of structural DNA discontinuities by DNA‐dependent protein kinase catalytic subunit. FASEB J. 19, 704–715 (2005)