Strand separation is a fundamental molecular process essential for the reading of the genetic information during DNA replication, transcription and recombination. However, DNA melting in physiological conditions in which the double helix is expected to be stable represents a challenging problem. Current models propose that negative supercoiling destabilizes the double helix and promotes the spontaneous, sequence-dependent DNA melting. The present review examines an alternative view and reveals how DNA compaction may trigger the sequence dependent opening of the base pairs. This analysis shows that in DNA crystals, tight DNA-DNA interactions destabilize the double helices at various degrees, from the alteration of the base-stacking to the opening of the base-pairs. The electrostatic repulsion generated by the DNA close approach of the negatively charged sugar phosphate backbones may therefore provide a potential source of the energy required for DNA melting. These observations suggest a new molecular mechanism for the initial steps of strand separation in which the coupling of the DNA tertiary and secondary interactions both actively triggers the base pair opening and stabilizes the intermediate states during the melting pathway.