<p>mRNA technology, which has enabled the rapid development of vaccines for infectious diseases, also holds great promise for a new generation of therapies for a host of rare and common diseases. A decade of clinical trials are beginning to clarify the key barriers to unlock the transformative potential of mRNA drugs, which are being addressed with novel interdisciplinary technical advances that, in some cases, are integrating the fields of gene, cell and mRNA therapies. Here, we review the scientific insights from a select group of clinical studies on mRNA-based drugs, including enzyme replacement therapies for rare diseases, cancer immunotherapies, genome-modifying therapies, and immune cell reprogramming therapies for cancer and autoimmune diseases. Several innovative approaches such as clinically tractable in vivo delivery systems, the development of completely ‘immune-silent’ mRNA–vehicle formulations that allow repeated administration and the development of approaches for preferential delivery to organs other than the liver would expedite the development of mRNA therapeutics 2.0.</p>