It's hard to say in which situation the Calvin Comfort theory is the most effective. Most likely, it's when things seem to be good and then they head south that you'd want to induce a little Calvin. I mean, when things seem like they're just a disaster, they usually turn out to be not as bad as they were perceived. (Well, not at first. At first, a disaster is a disaster. But in taking time for a second or a third look, you might see that it wasn't as bad as you'd thought.) Now, when things are good and then turn not so good, it's harder than things that just suck from the beginning.
When it goes from good to not so good for reasons that seem to indicate it can't be better until it's worse, well, that's even harder. That's when you're going to need something other than continually, questioning or wondering WTF? That's when you need to stop trying to figure out why and just try to figure out how. How to deal. How to cope. How to help.
And while Calvin can't fix it either (because it might not be something that's fixable or sometehing that really even needs fixing), he can help you find perspective through words that are oddly inspiring, considering that they come from a comic strip kid who talks to a stuffed tiger that talks back. 
Calvin's one sentence statement to Hobbes below sums up exactly how things feel when they seem to be not so great; things feel as if nothing that we have going for us is making a difference at that particular time; not even our lucky rocketship underpants. But Hobbes knows that not everything out there is able to be impacted by us. And he knows that sometimes it's not going to matter what we do because it's not a matter of doing, it's a matter of waiting. And that makes sense.

It seems to help, even if just a little bit, because if Hobbes can see that Calvin wishes that things were different, that's enough for us to hope that someone else will notice that we wished that things were different too. And just like how Hobbes is there for Calvin, and Calvin is there for us, it makes us want to let someone else know that we're there for them. Whether it's just taking time to listen or making sure that they know we're their friend or that we just wish we could help things to get better, there's that hope that it's known that we want it to be different too, and we'll stand by 'em while they figure things out. With or without our underpants. 