I (heart) panels, and my clients are crazy for them. It's simply the most intuitive way to handle content layout.
All of the recent projects I've worked on have been designed around making panels fit in easily. One of the tricks I've discovered is a simple technique to use in template.php for keeping some block regions around (e.g. regions in the header/footer area, useful for nav, banner ads, etc) even when using the "Disable Drupal blocks/regions" checkbox from the Advanced pane.
Here's the code: