I remember really loving her SXSWi keynote some years ago on human-computer interaction. There was a big overflow room because her talk was standing room only. I took away from that the conviction that we shouldn't design software for who we are but have to think with compassion about the experience of people who don't love computers. And that this shouldn't be looking down on people but instead recognizing their points of view (especially frustration). There's a good summary of that talk here:
http://blog.brian-fitzgerald.net/kathy-sierra-sxsw-keynote