Technical issues:
1. Trigger: Especially since everyone is using STANAG compliant mags, it's hard to set up the magwell and receiver reasonably close to the grip; this forces the grip farther forward (unusually long pull of stock), and also means that trigger mechanisms have to be a lot longer than conventional setups. The SAR-21 gets around this by using a rigid transfer plate, and the F2000's trigger is reportedly decent.
2. Ejection: The F2000 has the best solution so far by simply ejecting forward, but that makes some people leery. What if you get mud in it?
3. Kabooms: The SAR-21 takes the smart way out, and the section where your face would go is made out of lots and lots of Kevlar.
Ergonomic issues:
1. Reloading: It's slower for people who are used to receiver-forward designs, but it really seems to be a matter of training.
2. Balance: This one's weird. A good bullpup is almost center-weighted, but this means that people who are used to receiver-forward balance (forward-weighted) think it's ass-heavy. In design, you have to be careful to not to put too much stuff in the back anyway.
3. Sight axis: sights are often pretty high above bore axis. This isn't necessarily a bad thing, though, since it means that the bore axis goes lower into your shoulder and the weapon becomes more controllable.
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I think it would be interesting if someone tried making an entirely new, straight round (similar to the 5.7x28, but bigger) so that they could do a top-feeder similar to the P90. Go to a quad-stacked column past the feed ramp, and you could get a LOT of capacity into the thing without making it impossible to fire from prone.