Metastasis is the leading cause of cancer mortality. Chromatin remodeling provides the foundation for the cellular reprogramming necessary to drive metastasis. However, little is known about the nature of this remodeling and its regulation. Here, we show that metastasis-inducing pathways regulate histone chaperones to reduce canonical histone incorporation into chromatin, triggering deposition of H3.3 variant at the promoters of poor-prognosis genes and metastasis-inducing transcription factors. This specific incorporation of H3.3 into chromatin is both necessary and sufficient for the induction of aggressive traits that allow for metastasis formation. Together, our data clearly show incorporation of histone variant H3.3 into chromatin as a major regulator of cell fate during tumorigenesis, and histone chaperones as valuable therapeutic targets for invasive carcinomas. Display omitted •Metastasis inducers lead to a decline in CAF-1 suppressing canonical H3 incorporation•EMT and metastatic colonization occur as a function of CAF-1 levels•Histone H3.3 variant is essential for tumor progression and aggressive phenotypes•HIRA-mediated H3.3 gap filling induces a pro-metastatic transcriptional reprogramming Gomes et al. reveal metastatic stimuli reduce histone H3.1/H3.2 deposition on chromatin by suppressing the CAF-1 complex in breast and NSCLC cancer cells, leading to increased incorporation of non-canonical histone H3.3, which in turn induces chromatin remodeling and expression of metastatic genes.