The main things to remember, I think, is that skill ratings--or effective skill ratings--are the key to balancing challenges and encounters.
Somebody posted a chart a while ago that laid out the probabilities of different rolls, and it would be good to study it to get an idea of where you should place a difficulty--a player has about an 81% chance to roll a -1 or higher, for instance, so -1 is a good place to set a difficulty for something that's going to be a sure thing barring a freak occurrence. Conversely, the player's only got about a 19% chance of rolling a +2 or better, so that's where you'd set a difficulty if something's meant to be really tough for them to pull off.
The rulebooks talk a lot about setting opposition based on refresh, but frankly all the powers in the book aren't going to do much good if the enemy is rolling all his attacks and defenses from 1 or 2, while a PC with a 5 in attack and defense can get by pretty well without any powers at all.
The other key is compels--you should tailor scenarios such that they're going to be compelling the PCs aspects frequently, to draw them in and make things interesting. Compels are the grease that keeps the plot wheels turning. Before you start, go over with your players what their aspects mean, and how they can be compelled. And encourage them to self-compel.
Only roll if failure is going to be interesting to you and the players. Otherwise, let it slide, or throw in a compel to make it interesting.
And last but not least, remember that nearly
everything that happens is the result of a discussion between you and the players. There is, occasionally, room for GM fiat and Rule Zero, but for the most part, taken outs, concessions, compels, plot points, they should all be discussed with the players so that it makes sense and is satisfying.
At the same time, don't get overly attached to the plot you have in mind--good players can and will change it, and inspire you to change it. Be ready to say, "You know, that's cooler than what I had in mind, so let's go with that."