He is talking about "work on stuff that matters". To me the most important part in his posting is the break where he points out how to find "stuff that matters" for your self.
Some of you may end up working at highflying companies. Some of you may succeed, and some of you may fail. I want to remind you that financial success is not the only goal or the only measure of success. It's easy to get caught up in the heady buzz of making money. You should regard money as fuel for what you really want to do, not as a goal in and of itself. Money is like gas in the car -- you need to pay attention or you'll end up on the side of the road -- but a well-lived life is not a tour of gas stations!
Whatever you do, think about what you really value. If you're an entrepreneur, the time you spend thinking about your values will help you build a better company. If you're going to work for someone else, the time you spend understanding your values will help you find the right kind of company or institution to work for, and when you find it, to do a better job.