It depends on your primary motivation.
If it's collecting games as a monetary investment, then buy only Factory Sealed games (and even then, be very selective). If you're psychic, or a good enough guesser that you know, mostly, which games will be worth more than they were when you bought them, then sure. But if you're going to do that, you might as well be buying real restate or stamps or swords or something with a bit more history behind it.
If you are collecting them primarily because you like to collect, and you've had enough of coins or trading cards or whatever, then sure, whatever it is that you like. If they're mostly for display rather than resale value, then unsealed mint games are a great way to get lots of games very cheaply, especially if you're mostly buying one or two generations behind.
If you are collecting them mostly to *play* them, then buy them however you can get them, in whatever condition you will be satisfied with. Mint is fine - only a tiny fraction of madmen like us have things *better* than mint (which is of course, Factory Sealed).
If you want to do more than one of these things, then do both. That's what I do - I buy a copy to keep sealed, and then buy another to open and play (sometimes later at a lower price, sometimes right away).
One last point, though, is that if you think it's a good idea to speculate (that is, buy games specifically with the intention of selling them later at a profit), that history show two things:
1. You have to buy the games when they first come out anyway. Like almost all markets, price is determined by perceived value, and that is very often determined mostly by rarity. Thus, the rarest games are the most valuable, and those games are typically rare because of one of two factors (or usually, both). These are A. if the game was any good, and B. if the game was produced in limited quantities (and not made available again). If the game was produced in limited quantities (most of the most valuable games were), then it means that you probably can't get one at less than retail prices, and even then, only at launch. In other words, you'd better be a good guesser, because two or three bad guesses will almost certainly wipe out the profit potential of almost any good guess.
2. If you're buying them at launch with an aim to make money, you will always make more by keeping them sealed. Since your investment is the same (rare game have to be bought at full price), if you aim is to make money, you might as well make *more* money by keeping them sealed. If you want to play the game as well, then rent, or buy a used/loose copy.
Overall, games are poor (monetary) investments though. Sometimes, games can spike in value (copies of Metal Gear Solid, despite wide initial circulation, went up in price once the release of Metal Gear Solid 4 was imminent, and Ice Climbers jumped when Super Smash Bros. Melee was announced), but they can rapidly fall just as easily (such as when copies of Phoenix Wright were re-issued, or when Megaman X Collection was released). Sometimes, games simply rise in value bit-by-bit endlessly because more and more collectors get their hands on them and don't let go (Chrono Trigger), or peak quite high and then fall back to ordinary prices after that because they gradually circulate among everyone who was interested in playing them (original Gunstar Heroes). Sometimes prices go temporarily berserk due to a popular culture reference (Zero Wing) or movie (Iron Man), where prices go high because people try to buy them, and then fall right away because thousands of people have them lying around and decide to cash in (as opposed to previous scenarios where there are not too many copies rejoining the market after the spike, so they stay valuable). Some are so rare they they leave the market altogether (usually promos or prototypes), or become so common they're given away (many kinds of loose games over the years). Ultimately though, most games gradually drop in value to just about nothing, and in this age of legitimate emulation (Virtual Console, XBox Live! Arcade & XBox Originals, PlayStation Network, GameTap, Steam, etc) plus the rise of re-releases and classics collections (GBA in particular was single-handedly responsible for many NES and SNES games becoming almost worthless, and there have been so many collections with major Sonic The Hedgehog games on them that they're almost worthless too), not to mention that older generations of gaming hardware become harder and harder to maintain (most surviving NES consoles are very difficult to keep working, and I doubt that many Saturns or XBox 360s will survive for 50 more years, not to mention that even in the PC world, game compatibility spanning more than a decade is rare), games can very easily suddenly lose value even when they've been increasing in value for years.
Oh yeah, and also, most of the games that will be rare and valuable may very well not be games that you are the least bit interested in playing (don't like JRPGs? Tough - many of the most valuable games are JRPGs, especially from the 16-bit era). If you're buying the games that you like, your best chance of them keeping as much of their value as possible is if they stay sealed (although, if you're mostly buying games that you like, then it's probably because you want to play them, which requires that you open them).
Basically, you have to notice these sorts of things if you want the games to be (monetary) investments, but it can become so much like work, it stops being a hobby and actually does become a true investment.
