When an mRNA enters into the RNA degradation pathway called RNA interference (RNAi), it is cleaved into small interfering RNAs (siRNAs) that then target complementary mRNAs for destruction. The consequence of entry into RNAi is mRNA degradation, post-transcriptional silencing and in some cases transcriptional silencing. RNAi functions as a defense against transposable element and virus activity, and in plants, RNAi additionally plays a role in development by regulating some genes. However, it is unknown how specific transcripts are selected for RNAi, and how most genic mRNAs steer clear. This Current Opinion article explores the key question of how RNAs are selected for entry into RNAi, and proposes models that enable the cell to distinguish between transcripts to translate versus destroy.