To me it would really hinge upon what you mean by retro -- I'd probably draw the line of design at '84, which is when the 'game changers' were introduced... Affordable PC clones, the Mac, and early GUI's.
I always thought it would be cool to make the ultimate pre-PC era machine using the best of all the machines of the '76 to '84 timeframe...
For example start out with the Brutus of cheap home computer CPU's, the TMS9900 out of a TI... and instead of neutering it as they had done, actually give it the SRAM it should have instead of a crappy little 'scratchpad'. (though the 32k total memory limit is a bit of a pain -- map a port for rom swapping?) A close second choice for me would be the 6809, which was also "partly 16 bit" in a 8 bit era.
For a video chip, look no further than the VIC=2. 8 hardware sprites PER SCANLINE, 320x200 in 16 colors... You put a real processor instead of the anemic tired old 6502 behind it, you'd really have something.
Floppy drive would have to be standard/included... and I'd probably go with 80 track 5.25" -- I had a trio of those in two-thirds height on a Model III at one point... which at 720k a pop was 'absurd' storage for the time. I knew a few TRS-80 guys who had quartets of them in model III's with LDOS accessing them as 10 sectors per track -- they thought hard drives were a dead end since they had two megabytes of swappable storage vs. the 10 megabyte norm for a fixed disk at the time.
Of course, just to be different, I'd put Pascal in ROM instead of Basic... alongside a real 'editor' (that could do double duty as a WP). We rag on the Commodore "Minus 60", but the idea of in-ROM apps in that timeframe has some appeal.
From an aesthetics/layout/engineering point of view -- there is ZERO question in my mind about the keyboard. Buckling spring or NOTHING! Mind you, I'm sitting here using my i7 870 with 16 gigs of RAM and 7.5tb of disk space with a Model M (1993 case, 1987 board, 1989 mechanicals -- pieced it together from the best parts from three different ones)... so I'm a bit jaded on the subject of keyswitches. Honestly if I wasn't so concerned with it looking stock, I'd be modding one of my spares to work on my Tandy 1000 SX. I would also have a replaceable goretex or leather pad/rest in front of the keyboard. Some cheap doo-dads like leather trim go a long ways.
The case should be stamped SECC steel construction, with one twist... Chrome it. I just love the look of chrome.
I'd keep the keyboard separate from the system -- while I have a love of the all-in-one's, the difficult in expanding such systems was always a drawback unless you made them 'huge' like the Apple II... or you had the unreliable 'ribbon cable' approach like the TRS-80 Model 1. Expansion cards would be what in the PC era we'd call two-thirds length, the overall case size being about the same as an original tandy 1k -- so a bit smaller than a IBM. More than large enough for a pair of 2/3rd height drives, a decent power supply, a rather hefty mainboard, and five or more expansion slots. I would NOT integrate all that much into the mainboard, and may be tempted to take a queue from zenith/heathkit and S100 systems and make EVERYTHING socketed with the mainboard being a passive backplane... could even make it a mini-tower... not exactly retro, but it is a bit more sensible a design if you're not putting the system on the desk.
Did I mention it should be chromed?
Faceplate should be removable, all blockoff plates for empty bays should be pre-cut out and screwed on -- front and back. I would probably add standard faceplates the entire front-length even if there's not space for drives, to allow custom panels to be made for things like sound, temperature monitors, front facing ports, etc.
A standard joystick interface should also be included, and I would provide inputs for both analog and digital sticks -- digital would of course use the atari 9 pin plug (you'd be #DDD not to) which also allows for two 'paddle' lines, which could just as easily be an analog stick. Would be funny actually to make a controller for a retromachine using the 9 pin atari interface that has a analog stick on one side and a digital on the other, just like a modern controller. In terms of actually reading the analog inputs I'd follow the TRS-80 color computer's example and use a 6 bit ladder DAC (a few cents worth of resistors) and a comparitor -- wiring the pots to both +5 and ground, sensing off middle. Output 50%, compare... +/- 25%, compare, lather, rinse, repeat until you have a match... resulting in a maximum of 6 operations to read it instead of a endless loop. 0..63 is probably overkill for an analog joystick range on such a system.
STANDARD RS-232 and Centronics parallel would also be a 'must have' -- full capability on them too, no cheaping out on slow half-assed serial/bit-banging and none of that 'uni-directional' nonsense on the parallel. (Do you hear me Tandy?!?)
Another idea would use a bit later hardware... I always thought it would be cute to take the motorola 68K and Z80 pairing found in systems like the original Mac and TRS-80 Model 16, and mate them to a kick-ass video generator like say a Yamaha YM7101... could give it 64k of system RAM, 64k of video RAM, another 8k scratchpad dedicated to the Z80... little 2k startup ROM, something like a YM2612 FM chip for synth backed up by a TI PSG...
OH WAIT -- that's called a Sega Genesis/Mega Drive... Always wanted to add a keyboard and turn that into a real computer. You put a meg of RAM on that and give it a keyboard and fixed storage solution, it would have been a hot little computer for the time-frame... basically a big brother for the SC-3000.