Homologous recombination is a DNA repair mechanism that uses the genetic information of a homologous DNA sequence as template for repair of a DNA break. The genetic consequences of recombination depend on the choice of the molecule used as template. While sister-chromatid recombination (SCR), which uses as template for repair the identical and intact sister chromatid, preserves genome integrity, allelic and ectopic recombination can compromise it. SCR is, thus, the most secure mechanism of recombinational repair. This, together with the fact that most DNA breaks may appear spontaneously during replication, makes SCR the major recombination event occurring in mitotic cells from yeast to mammals. Given its physiological relevance, we review here the current knowledge about the mechanism(s) of SCR as well as the genetic and molecular factors controlling it, and how this knowledge open new perspectives to our understanding of genome dynamics.