A genetic screen was designed in Drosophila to interrogate its genome for mutations sufficient to cause noninvasive tumors of the eye disc to invade neighboring or distant tissues. We found that cooperation between oncogenic Ras V12 expression and inactivation of any one of a number of genes affecting cell polarity leads to metastatic behavior, including basement membrane degradation, loss of E-cadherin expression, migration, invasion, and secondary tumor formation. Inactivation of these cell polarity genes cannot drive metastatic behavior alone or in combination with other tumor-initiating alterations. These findings suggest that the oncogenic background of tissues makes a distinct contribution toward metastatic development.