Therapeutic applications of gene delivery have so far relied on the introduction of foreign DNA, an approach that carries a risk of harmful genomic integration. Wroblewska et al. have now created RNA-only synthetic regulatory circuits using RNA-encoded RNA-binding proteins and demonstrated their functionality in mammalian cells. They engineered a multi-input cell-type classifier, encoded as modified RNA, that can distinguish HeLa cells from other cell types in a fluorescence assay on the basis of their microRNA expression profiles. By incorporating a pro-apoptotic gene as the circuit output, they were able to selectively kill HeLa cells in a mixed-cell population without affecting the viability of other cell types. The researchers also constructed a repression cascade and a switch circuit, which were functional when encoded on modified RNA or self-replicating RNA, facilitating transient or long-term expression, respectively. The researchers suggest that RNA circuits offer potential benefits for applications in vivo, particularly those in which safety is a concern.