Lipid nanoparticles (LNPs) for nucleic acid delivery often use novel lipids as functional excipients to modulate the biodistribution, pharmacokinetics, pharmacodynamics and efficacy of the nucleic acid. Novel excipients used in pharmaceutical products are subject to heightened regulatory scrutiny and often require data packages comparable to an active pharmaceutical ingredient. Although these regulatory requirements may help to ensure patient safety they also create economic and procedural barriers that can disincentivize innovation and delay clinical investigation. Despite the unique structural and functional role of lipid excipients in LNPs, there is limited specific global regulatory guidance, which adds uncertainty and risk to the development of LNPs. In this Perspective we provide an industry view on the chemistry, manufacturing and controls challenges that pharmaceutical companies face in the use of novel lipid excipients at each stage of development, and propose consensus recommendations on how to streamline and clarify development and regulatory expectations.