RNA-based synthetic genetic circuits provide an alternative for traditional transcription-based circuits in applications where genomic integration is to be avoided. Incorporating various post-transcriptional control methods into such circuits allows for controlling the behaviour of the circuit through the detection of certain biomolecular inputs or reconstituting defined circuit behaviours, thus manipulating cellular functions. In this review, recent developments of various types of post-transcriptional control methods in mammalian cells are discussed as well as auxiliary components that allow for the creation and development of mRNA-based switches. How such post-transcriptional switches are combined into synthetic circuits as well as their applications in biomedical and preclinical settings are also described. Finally, we examine the challenges that need to be surmounted before RNA-based synthetic circuits can be reliably deployed into clinical settings.