Building third party flakes takes forever since every flake uses its own version of nixpkgs. If you don't pin your third party flake urls they might also change under your nose as you run the same command again a day later.
Flakes are coupled to git. You need to remember to stage changes whenever you do Ctrl+S in your editor before rebuilding. I've wasted more time than I'd like to admit wondering why what I'm building doesn't include my latest change.
Flakes copy the entire directory into the nix store. This is terrible for mono-repos - and especially if it contains any large files. There is an issue about making the copying of the entire directory into /nix/store lazy - though this doesn't really address the problem. It just treats some common symptoms.
This kind of copying would likely be a lot more acceptable if it was specified explicitly in flake.nix, rather than implicitly. Then you could also use your own filters for ignoring files, rather than relying on the coupling to git and its staging area.