DNA hypomethylating agents such as decitabine are used to treat myeloid cancers and are thought to work by reactivating tumour suppressor genes that have been silenced by DNA methylation. However, cancers become resistant to these drugs, and this may be due to gene re-silencing. These authors provide evidence that re-expression of the MLH1 tumour suppressor gene in colon cancer cells following decitabine treatment involves both DNA demethylation and nucleosome eviction at promoters. Importantly, after decitabine withdrawal, the initial step in re-silencing is nucleosome reassembly, which occurs before remethylation — a finding with implications for combatting drug resistance.