There is a great need in biomedical and genetic research to detect DNA damage and de novo mutations, but doing so is inherently challenging because of the rarity of these events. The enormous capacity of current DNA sequencing technologies has opened the door for quantifying sequence variants present at low frequencies in vivo, such as within cancerous tissues. However, these sequencing technologies are error prone, resulting in high noise thresholds. Most DNA sequencing methods are also generally incapable of identifying chemically modified bases arising from DNA damage. In recent years, numerous specialized modifications to sequencing methods have been developed to address these shortcomings. Here, we review this landscape of emerging techniques, highlighting their respective strengths, weaknesses, and target applications.