Most human tumors display inactivation of the p53 and the p16^INK4/pRb pathway. The Ink4a/alternative reading frame (ARF) locus encodes the p16^INK4a and p14^ARF (murine p19^ARF) proteins. p16^INK4a is deleted in 40–60% of breast cancer cell lines, and p16^INK4a inactivation by DNA methylation occurs in ≤30% of human breast cancers. In mice genetically heterozygous for p16^INK4a or Ink4a/Arf, predisposition to specific tumor types is enhanced. Ink4a/Arf^+/− mice have increased Eμ-Myc-induced lymphomagenesis and epidermal growth factor receptor-induced gliomagenesis. ErbB2 (epidermal growth factor receptor-related protein B2) is frequently overexpressed in human breast cancer and is sufficient for mammary tumorigenesis in vivo. We determined the role of heterozygosity at the Ink4a/Arf locus in ErbB2-induced mammary tunorigenesis. Compared with mouse mammary tumor virus-ErbB2 Ink4a/Arf^+/− mice, mouse mammary tumor virus-ErbB2 Ink4a/Arf^wt mammary tumors showed increased p16^INK4a, reduced Ki-67 expression, and reduced cyclin D1 protein but increased mammary tumor apoptosis with no significant change in the risk of developing mammary tumors. These studies demonstrate the contribution of Ink4a/Arf heterozygosity to tumor progression is tissue specific in vivo. In view of the important role of Ink4a/Arf in response to chemotherapy, these transgenic mice may provide a useful model for testing breast tumor therapies.