Various pathways by which damage to DNA can elicit a checkpoint response. DNA damage may occur as a result of many different kinds of damaging agents (for example, methyl-methanesulfonate (MMS), γ-rays and ultraviolet (UV) light). Alternatively, spontaneous damage occurs during normal cellular metabolism, for example, from the production of reactive oxygen species or failed catalysis by DNA topoisomerases (Top1/Top2). These lesions can be repaired without activating checkpoint responses; however, the processing of many of these DNA structures generates single-stranded DNA, the salient intermediate in the DNA-damage checkpoint response. In fact, double-strand DNA breaks can also lead to stretches of single-stranded DNA at their ends before homologous recombination commences. The papers by Workman et al. [3] and Pan et al. [4] highlighted in this article describe many of the common pathways that give rise to or process DNA damage, and which trigger the checkpoint, as well as the pathways necessary for subsequent recovery. Abbreviations: BER, base excision repair; dNTP, deoxynucleoside phosphate; MMR, mismatch repair; NER, nucleotide excision repair; TCR, transcription-coupled repair; Tdp1, tyrosyl-DNA phosphodiesterase.