Significance The origin recognition complex (ORC) binds sites from which DNA replication is initiated. By mapping binding sites in human cells, we show that ORC binds selectively to open (DNase I-hypersensitive) regions containing active chromatin marks. There are far more ORC sites in early replicating regions of the genome, and computational simulation based on ORC binding indicates that replication timing is due primarily to ORC density and stochastic initiation of DNA replication from origins. Large genomic regions with a paucity of ORC sites are strongly associated with common fragile sites and recurrent deletions in cancers. Thus, replication origins, replication timing, and replication-dependent chromosome breaks are determined ultimately by the genomic distribution of activator proteins at enhancers and promoters.