Site-specific recombinases are important tools for genomic engineering in many living systems. Applications of recombinases are, however, constrained by the rarity of naturally occurring target sequences. A tremendous range of recombinase applications can be envisioned if the targeting of recombinase specificity can be made readily programmable (Chapter 1). To address this problem we sought to generate zinc finger-recombinase fusion proteins (RecZFs) capable of site-specific function in a diversity of genetic contexts (Chapter 2). Enzymes resulting from the direct fusion of zinc finger proteins and serine recombinase catalytic domains possessed cooperative DNA-binding and catalytic specificities. This class of RecZFs was found to integrate transgenes with >98% accuracy into the human genome (Chapter 3). These modular recombinases can be reprogrammed: new combinations of zinc finger domains and serine recombinase catalytic domains generate novel enzymes with distinct substrate sequence specificities. To further expand the number of potential target sequences, Substrate Linked Protein Evolution (SLiPE) was used to optimize the catalytic domains of the enzymes Hin, Gin, and Tn3 for resolution between non-homologous sites (Chapter 2). One of the evolved clones, GinL7C7, catalyzed efficient, site-specific recombination in a variety of sequence contexts. Following this template of rational design and directed evolution, RecZFs may eventually mediate gene therapies, facilitate the genetic manipulation of model organisms and cells, and mature into powerful new tools for molecular biology and medicine.