The key genetic process of DNA replication is initiated at specific sites referred to as replication origins. In eukaryotes, origins of DNA replication are not specified by a defined nucleotide sequence. Recent studies have shown that the structural context and topology of DNA sequence, chromatin features, and its transcriptional activity play an important role in origin choice. During differentiation and development, significant changes in chromatin organization and transcription occur, influencing origin activity and choice. In the last few years, a number of different genome-wide studies have broadened the understanding of replication origin regulation. In this review, we discuss the epigenetic factors and mechanisms that modulate origin choice and firing.