Dwarf Fortress is awesome, but has a famously difficult initial learning curve. I was thinking about this, and it occurs to me that there are some relatively small changes that would make it easier. So here are my thoughts, aimed at the things that tripped me up when I was learning and that seem to trip other people up, in roughly descending order of significance.
The first thing is figuring out what's going on, and the best solution I can think of is to revamp the loo(k) command. Make it so that while in the default state (no command active), hovering over a tile shows the look-list for that tile, above the commands list (which can be bottom-aligned instead of top-aligned). There's room for it now that most people are using big screens instead of 80x25. Then, take as much information from other menus as possible, and move or copy it into the look-list: eg show container/building contents indented under the container, show dwarf inventories indented under the dwarf (with hauled items and weapons sorted to the top), show a dwarf's current job and mood under the dwarf, show a workshop's current job under the workshop, show a tile's dig-designation if any, show forbid/dump/melt flags, show any burrows the tile is part of, show the stockpile, and show if the tile is a restricted area or has other non-default movement settings.
Then if the tile is clicked while in the default state, pause and go to look mode. While in look mode, pressing enter with a dwarf selected should go into (v) view unit mode, and pressing enter with a building selected should go into (q) building prefs mode, and enter with a stockpile selected would go into (p) stockpile mode. Clicking on a different tile would move the look-cursor to that tile, and clicking the same tile would be like pressing enter on the top item (so that double-click is a shortcut into the right menu). This obsoletes the 't' command.
The next thing that seems to confuse people is that the commands list has a lot of things in it, and it's not clear which ones are important and which ones are less-frequently used things that can be ignored at first. This can be solved by rearranging the menu, so that instead of being alphabetical, commands are sorted into approximate order of importance, and arranged in groups. I imagine it looking like this:
b: Building d: Dig
u: Unit List k: Look
p: Stockpiles i: Zones
a: Announcements r: Reports
m: Military s: Squads
o: Orders z: Status
j: Job List w: Burrows
n: Nobles and Administrators
c: View Civilizations
q: Set Building Tasks/Prefs
v: View Units H: Hot Keys
Tab: Move this menu/map
?: Help ESC: Options
;: Movies D: Depot Access
Space: Resume .: One-Step
Then you can say: don't bother with the second block of commands until you've figured out the first, and so on. (Note that I dropped the 't' command, which a better look command makes unnecessary, and the 'R' command, which I've never found useful. I also changed the description from "designate" to "dig", which is a little less accurate but clearer.)
In the dwarf labor screen (v-p-l), skill levels should be shown next to each labor (or the highest level in the category, for categories), as a number. And if you go from the (u)unit list to a dwarf, then pressing esc should bring you back to the unit list with the same cursor position, the way it is when you pick view-creature from there; that would go a long ways towards mitigating the need for Dwarf Therapist, by letting you go through the dwarves systematically to set their labors. The labor menu also probably ought to be more prominent; currently it's buried two levels deep. I'd split it out from the (p)refs section so that it's (v-l) instead of (v-p-l).
Over in the (b)uild menu, the entries which are categories (workshops, furnaces, traps/levers, siege engines) should be sorted on top, and things which can't be built because their requirements aren't met (eg beds when you don't have any) should be colored differently.
None of this will stop new players from having their Urists run into the goblin horde for a sock or flooding their fortress, but it should keep players from getting too frustrated before they have a basic fortress up and running.