Cancer cells are often characterized by copy-number alterations at specific regions of the genome, but little is known about how localized copy gain is achieved. Whetstine, Getz and colleagues now report that overexpression of the histone demethylase KDM4A in two different cell lines induces transient, localized copy gain without global chromosome instability. Analysis of The Cancer Genome Atlas data showed that KDM4A is amplified and overexpressed in certain cancers and correlates with poor outcome in ovarian cancer. Importantly, KDM4A-amplified tumors had increased copy gains for the same regions identified in cell culture. KDM4A-dependent copy gain was shown to require histone demethylase activity, and interference with H3K9 or H3K36 methylation promoted copy gain, whereas HP1γ overexpression antagonized it. KDM4A-dependent copy gain was induced in less than 24 hours and required S phase. These copy gains were not stably inherited and were cleared by late G2 by yet-unknown mechanisms. However, as these regions contain putative oncogenes, the transient copy gain could potentially promote tumorigenesis while masking the originating event. To gain insight into how KDM4A is involved in generating copy gain, the authors identified KDM4A-interacting proteins by mass spectrometry analysis and observed a significant enrichment for proteins involved in rereplication, including MCMs and DNA polymerases. Indeed, although KDM4A did not affect widespread rereplication, it did promote rereplication of a specific locus that exhibits copy gain. These observations were further supported by chromatin immunoprecipitation experiments indicating that KDM4A overexpression induces chromatin changes and recruitment of the replication machinery at this region. Although these studies raise many important questions, they begin to establish how copy-number changes could originate during tumorigenesis and the role of chromatin modifiers in this process. (Cell 154, 541–555, 2013)