A natural generalization of a crossing change is a rational subtangle replacement (RSR). We characterize the fundamental situation of the rational tangles obtained from a given rational tangle via RSR, building on work of Berge and Gabai, and determine the sites where these RSR may occur. In addition we also determine the sites for RSR distance at least two between 2-bridge links. These proofs depend on the geometry of the branched double cover. Furthermore, we classify all knots in lens spaces whose exteriors are generalized Seifert fibered spaces and their lens space surgeries, extending work of Darcy-Sumners. This work is in part motivated by the common biological situation of proteins cutting, rearranging and resealing DNA segments -- effectively performing RSR on DNA `tangles'.