First it was the absence of a way to develop software at all that frustrated developers after the iPhone debuted in 2007. But that’s nothing compared to the irritation some developers are feeling now about the ever-popular App Store.

This week found two high-profile Apple iPhone developers throwing up their hands and leaving the App Store in their rear view mirrors. First was Facebook programmer Joe Hewitt, who declared his surrender out of frustration with Apple’s approval process. (For the record, Hewitt isn’t leaving Facebook, he just won’t be working on the iPhone app.)

Rogue Amoeba marks the second defection, announced today in gory detail on their company blog. It’s a particularly surprising surrender coming from a longtime Mac developer known for such excellent software as Airfoil, Audio Hijack Pro and Fission. Developer Paul Kafasis makes it clear that the labyrinthine web of multiple submissions and re-submissions has finally taken its toll.

At issue is the obscene length of time it took Apple to finally approve a minor bug-squashing update to Rogue Amoeba’s Airfoil Speakers Touch: three and a half months! First submitted back in July, the app update was initially rejected for its use of “Apple-owned graphic symbols” — which had been featured and approved in the original version 1.0. But that was only the beginning of their troubles.

Fanning the flames of what could potentially become a full-on developer revolt down the road, Kafasis warns App Store users: “Be aware that Apple is acting as a gatekeeper, and preventing you from getting the software that developers such as ourselves are trying to provide you. We wanted to ship a simple bug fix, and it took almost four months of slow replies, delays, and dithering by Apple. All the while, our buggy, and supposedly infringing version, was still available. There’s no other word for that but ‘broken’.”

For his part, Facebook’s Hewitt summed things up nicely last night on Twitter: “For every dev that leaves iPhone in frustration, 1,000 new ones join up. iPhone is an unstoppable train regardless of how much we complain.”