I’ve created a new one based on Default, but whenever I create a new file or close/reopen the program it’s gone 
I usually save a Startup File (Ctrl+U), and I also save my User Preferences (Ctrl+Alt+U) after making any changes to the UI. Both options can be found in the File menu.
Thank you for answering @Miss_B!
So I make my interface and press ctrl+U? will it be there the next time i open Blender?
Hi Tammy, I had to respond to the email I received from GameDev.tv because
I’m having problems logging into the forum.
Ctrl+U will save the Startup File. Blender, like a lot of 3D software I
use, will use the Startup File the next time you open Blender.
I would also suggest you use Ctrl+Alt+U to save your User Preferences, as
that should definitely control how your UI looks and responds every time
you open Blender. Both of these options should guarantee your changes have
been saved. If you ever decide to make more changes, just save your User
Preferences each time, and you should be good to go.
Thank you! I changed the theme and saved 
I hope it will be there the next time i open 
Have a lovely day!
You can customize a lot of things through User Preferences and save with the Start-Up file. I am a point and click girl so usually save my set-up via clicking on File menu then Save Start Up file. My start up file has a lot different items set based on how I work, such as I have Cycles set as my default renderer. I have the node and UV editors at the bottom where the default timeline usually is. The default cube that opens with Blender is long gone :-). I have my measurements units set-up for metrics, a work space, theme, …you can go on and on and on with how you set up your work space.
YAY! I’ve finally able to log into the forums again. Have no idea what was going on, but I’m baaaaaack! 
Anyway, I’m like you Morgaine, though I do use shortcuts a lot, the User Preferences is one instance where I click on the File Menu. I don’t have Cycles set as my default renderer, mostly because I don’t usually do final renders in Blender, but I do have the Node Editor on the bottom of my workspace, instead of the default timeline as, again, I don’t usually do animations. I, too, got rid of the default cube years ago.
When I’m working with the UV Editor, however, I like to split my screen in half so I can have my mesh in Edit mode on the left, and the UV mapping on the right. I prefer that rather than having to go back and forth between screens, which I only do when I have to zoom in closer to be sure I’m working with the correct portion of the UV map.
Woot! Glad you could log in again and are back!
My mind is too full of short cuts from to many different software packages I seem to use on a daily basis and no always fun ones either. I always inadvertently use the wrong short cuts in the wrong program at the wrong time and wonder why something is not working LOL. So, is thankful for point and click when possible.
See, is a great thing Blender allows us to set up our work spaces specifically for our style of doing things. One of the first things I usually set is the dpi so I can actually see all the buttons and text! Not all software allows you you to do that! Having a split screen in the Viewpoint, for me at least, is confusing and just clutters things up and annoys me even though I am running a 27 inch monitor. It works out well at the bottom since it is rare I use the timeline and is easy enough to change it if need. I like the UV editor at the bottom to void distraction and tend to use the Sync function in the editor.
The one question I have is, how do you save the Start UP file and/or your preferences so you can use it with newer versions of Blender? I have become quite apt at quickly being able to manually set-up a new version but, I am assuming there is an easier way.
Hey Morgaine, are you on Windows or Mac? I’m on Win7 Pro, so if you’re on a Mac, I wouldn’t be able to help you.
That said, with Windows, if you go to C:\Users\your computer name\AppData\Roaming, you will find a folder called Blender Foundation.
Within that folder you’ll have to navigate to the following folder: Blender > 2.78 > config, and within the config folder you should find 4 files.
- bookmarks.txt (if you use that)
- recent-files.txt
- startup.blend
- userpref.blend
I think that folder will remain intact if you update, but to be sure, I usually copy the config folder to my desktop, update Blender, and then replace the “new” config folder (if the content was changed) with the config folder I saved to my desktop.
Thanks, Miss B,
Your instructions were very clear and found the information I needed on my Mac
Mac Library > Application Support > Blender > 2.7X (I have multiples versions on my computer) > config…then it lists the 4 files!
Now, if I can just remember this next time I updated Blender!
Yes, the remembering is always the hardest part, especially for someone in my age range. 
Now that I think of it, except for the fact the recent-files and bookmarks files won’t update unless you have them in that folder, you could always save a copy of that folder elsewhere on your hard drive. That way, if you forget and the update changes the files, you can always search for that folder and THEN replace the changed one. I’m sure, if you’re like me, you have a folder where you keep stuff that you access often enough to remember it exists.