The RUNX family transcription factors are critical regulators of development and frequently dysregulated in cancer. RUNX3, the least well characterized of the three family members, has been variously described as a tumor promoter or suppressor, sometimes with conflicting results and opinions in the same cancer and likely reflecting a complex role in oncogenesis. We recently identified RUNX3 expression as a crucial determinant of the predilection for pancreatic ductal adenocarcinoma (PDA) cells to proliferate locally or promulgate throughout the body. High RUNX3 expression induces the production and secretion of soluble factors that support metastatic niche construction and stimulates PDA cells to migrate and invade, while simultaneously suppressing proliferation through increased expression of cell cycle regulators such as CDKN1A/p21 . RUNX3 expression and function are coordinated by numerous transcriptional and post-translational inputs, and interactions with diverse cofactors influence whether the resulting RUNX3 complexes enact tumor suppressive or tumor promoting programs. Understanding these exquisitely context-dependent tumor cell behaviors has the potential to inform clinical decision-making including the most appropriate timing and sequencing of local vs. systemic therapies.