Genomic instability is characteristic of malignant cells, and a strong correlation exists between abnormal karyotype and tumorigenicity. Increased expression of the homologous recombination and DNA repair protein Rad51 has been reported in immortalized cell lines and multiple primary tumor cell types which could alter recombination pathways to contribute to the chromosomal rearrangements found in these cells. In addition, Rad51 participates in a complex network of interactions that includes DNA damage sensors, tumor suppressors, and cell cycle and apoptotic regulators, and mutation of many of these proteins have also been associated with tumor initiation or progression. Insights into the connection between disregulated Rad51 and malignant phenotype indicate that Rad51 is a potential target for new anti-cancer regimens including those that use siRNA technology.