To shed light on the relationships between over-expression of anti-apoptotic proteins, genomic instability, and the metastatic ability of breast cancer cells, we analyzed genetic changes in tumors and metastases by orthotopically injecting MDA-MB 435 cells transfected with anti-apoptotic genes Bcl-x_L or Bcl-2 into nude mice. Tumors and metastasis variants were extracted by primary culture from breast, bone, lung, and lymph node from mice with 435/Bcl-x_L, 435/Bcl-2, and 435/Neo tumors. Using the Arbitrarily Primed Polymerase Chain Reaction (AP-PCR), which permits the detection of allelic imbalances, we generated four different fingerprints utilizing four primers. We found that the genetic damage fraction (GDF) increased in 435/Bcl-2 (GDF=0.55) and 435/Bcl-x_L cells (GDF=0.34), in regard to 435/Neo control cells (GDF=0.29), indicating that non-random genetic alterations occurred in cells secondary to Bcl-2 or Bcl-x_L over-expression. Anti-apoptotic proteins render breast cancer cells susceptible to the in vivo acquisition of highly tumorigenic (Kruskal–Wallis, P=0.019) and metastatic (Kruskal–Wallis, P=0.004) activity. We therefore propose that genetic instability is a molecular mechanism favored by anti-apoptotic proteins involved in the selection of highly metastatic cells during tumorigenesis, a pathogenic event favoring the expansion of metastasis.