The genome, which is an organism’s complete genetic blueprint, consists of a dynamic mixture of unique and repetitive DNA sequences that are continuously evolving, making the human genome a prime example of this complexity. Repetitive sequences emerge through mechanisms such as replication slippage, transpositions, and unequal recombination, whereas non-repetitive sequences evolve through point mutations, insertions and deletions, segmental duplication errors, and horizontal gene transfers. This review explores the evolution of polymeric nucleic acids, genome proliferation and homeostasis, and the various mechanisms that drive genomic diversity. It further highlights the occurrence and biological significance of DNA repeats across different domains of life. In addition, the review critically evaluates the impact of these sequences on genome instability, regulatory processes, and their involvement in human diseases. The concluding sections integrate current evidence on the contribution of repetitive elements to evolution, focusing on the interplay between genetic and epigenetic mechanisms that govern their fate, and emphasize how this knowledge is crucial for advancing genome function research and personalized medicine.