Another example of this, maybe less important but still notable, is the defiance of many states over Federal scheduling of cannabis (a C-I drug, therefore "totally illegal"). While the FDA claims jurisdiction over all drugs, probably using the Interstate Commerce Clause (be advised, IANAL), the states have looked at cannabis as a states rights issue. Right now, I think they are avoiding really big legal trouble by using a few loopholes (e.g. MN is deriving its delta-9-THC and other cannabis products from industrial hemp, a fairly inefficient process). Outside of Native American reservations, I'm not sure that any state is actually selling anything like cannabis flower. But it is real defiance on the part of many states, since delta-9-THC and other cannabinoids are the substances which are actually scheduled and regulated by the FDA, and they have really pissed off the Feds with their actions. I don't think you would have seen this at an earlier time in US history, and it's an interesting development.

Then there's the Covid response, or lack of it, mostly thanks to the chuds turning it into another front in the culture war. That's also one for the history books.