Electronic nicotine delivery systems (ENDS) continue to rapidly evolve. Current products pose unique challenges and opportunities for researchers and regulators. This commentary aims to highlight research gaps, particularly in toxicity research, and provide guidance on priority research questions for the tobacco regulatory community. Disposable flavoured ENDS have become the most popular device class among youth and may contain higher nicotine levels than JUUL devices. They also exhibit enhanced harmful and potentially harmful constituents production, contain elevated levels of synthetic coolants and pose environmental concerns. Synthetic nicotine and flavour capsules are innovations that have recently enabled the circumvention of Food and Drug Administration oversight. Coil-less ENDS offer the promise of delivering fewer toxicants due to the absence of heating coils, but initial studies show that these products exhibit similar toxicological profiles compared with JUULs. Each of these topic areas requires further research to understand and mitigate their impact on human health, especially their risks to young users.