After over four years of working with Drupal, I have finally reached one of the major goals that I have envisioned from the beginning. Today I released the first beta of Panels Everywhere, a new module that works with Panels and Page Manager that allows you to never use the block management system again.
Instead, using the power of Panels, you can control the entirety of your system with Panel layouts. You still have all of the content available from blocks, but you also gain the rich content that you can get from using contexts, plus the power of selection rules that can do pretty amazing things. And when it can't do the one amazing thing you really need, most of the time the plugin to do that amazing thing isn't actually that difficult to write.
Now, this system isn't for the faint of heart. There's still a lot of adoption that needs to happen. In particular, I am really hoping for a theme or two to adopt this and provide some good basic layouts. Plus, Panels itself needs to improve more to ease a few pain points on the way. Fortunately, there are people out there, right now, actually using this tool and helping to identify these pain points, allowing us to fix them and get more experience building sites in this fashion.
The next step, I think, will be to build a distribution, now that drupal.org supports those, that includes everything needed to get started with Panelized Drupal. In order to accomplish this, I'll need a nice looking theme that can supply some layouts to Panels and is willing to run nicely without a page.tpl.php.
In any case, I'd love for folks to give this system a try and see how it works for them. Right now, because there isn't really a good theme, it looks pretty barren. But the point is that it lets you build the theme around it.