I love this question, because I struggle with some of the same ideas. I use this as a part time job and hobby, and while I don't need the income, it's really hard to keep defined lines on how much to invest, and how separate to keep my "LEGO" funds from my cash reserves, investments, etc. There's a tough balance in making sure you have cash to act on opportunity, and also always having it work for you. I've found something to be helpful, and I'll use two sets as an example.
Lego 76119 Batmobile Pursuit of the Joker - RRP $30 Widely Available $21-24
Lego 10260 Downtown Diner - RRP $170 Widely Available (kinda) $170
I think both of these sets will be great 2 years from now, and have purchased both in quantity. I have an expectation of a 100% return on both at that time(slightly higher on the Batmobile). However, I've been much more careful with the Batmobile, because it isn't a liquid set. If I had to sell because I overstretched myself, didn't want to pass up a unique opportunity, etc., after factoring in shipping costs and/or selling in bulk(I am limited to Ebay/Bricklink/local) I'd take a 25-35% hit on the Batman sets. If I needed to liquidate the Diner, I could do so at approximately a break-even point. If I have $500 sitting around that I'm considering putting into play, but could conceivably need later, I'm much more likely to buy 2 or 3 more Diners than a bunch of the Batmobile, even though I think the total ROI on the Batmobile will be better in the long run.
A bit of a ramble, but I enjoy thinking about this stuff.
Jesse