Mec1, the yeast orthologue of human ATR, is an essential protein kinase that regulates the DNA damage response following replication stress to maintain genome integrity. In this study, de Oliveira et al. used a quantitative mass spectrometry approach to study Mec1 signalling in vivo and found that it is robustly activated during normal DNA replication. Interestingly, this action is partially uncoupled from Rad53 activity, which is an effector kinase in the DNA replication checkpoint, and the authors showed that Mec1 targets proteins involved in transcription, RNA processing and chromatin remodelling. The authors propose that in addition to regulating the replication stress response, which involves Rad53, Mec1 functions during normal replication to positively regulate ongoing DNA synthesis.