Color
I used to teach color profiling and color management way back in my days with DuPont Color Proofing. There is a really long answer to your question and a 5000 foot view answer.
Simply put - RGB is a much wider color space than CMYK, so if you design in RGB you will have a larger pallette of colors to choose from and be able to achieve - on a
computer screen at least. The very minute you have to convert to CMYK (which at some point when printing digital - you will have to) you then clip the potential color gamut pretty good in certain areas and that clipping is generally based on the achievable gamut of whoever's ink you are using. Generally you take a great hit in Oranges, Reds, and Blues. There are others, but those are the big ones.
This is why when you choose Pantone 021 orange on screen you get a really bright orange - but when you print you get a brownish pumpkin orange. Lots of reasons go into this and why this happens.
Easy way to predict these shifts is to spen $90 on the Pantone Solid to Process book and you can see a swatch printed spot color right next to its CMYK equivalent and can see what happens when it gets converted to print process.
Most new RIP systems will do a pretty decent job of converting from RGB to CMYK for you. This allows you to carry the maximum gamut as far as you can go prior to ink on media. Or you can calibrate your monitor and set up some profiles and do the conversion yourself in Photoshop. Either way has plusses and minuses and its your decision which is right for you - just remember to not double color manage your images or you will get all kinds of funkiness.
If you want to get really squirrelly - design in LAB color. Different discussion...