Dare Obasanjo points out that design will trump a lot of other things, especially if you need to scale massively:

Scaling a service infrastructure is all about optimizations and trade offs. My original post wasn't meant to imply that Twitter's scaling problems are unsolvable since similar problems have obviously have been solved by other online services and Enterprise products in the messaging space. It was meant to inject some perspective in the silly claims that Ruby on Rails is to blame and give readers some perspective on the kind of architectural problems that have to be solved.

The only caveat I'd add is this: most applications don't have anywhere near the scaling demands of Twitter - which is why "architecture astronauts" can be dangerous.

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