This is a great question. I will answer in two parts
(1)What is the difference between the 4-3 defense and the 3-4 defense? 
On the left in red, we have a base 4-3 defense on the top lining up against your typical offensive line. On the right in red we have a base 3-4 defense. There are few differences to note.
(1) First, and most obviously in a 4-3 there are four down line men with one hand touching the ground. In the 3-4 there are three down line men. The remaining defenders in the box are made up of linebackers who at the hike of the ball are more or less standing upright.
(2)In the 3-4 the Nose Tackle(NT) is expected to demand the attention of two offensive line men. By doing so, the NT can in effect neutralize any potential running lane up the middle for the running back and/or create an opportunity for either the weakside or middle linebacker to attack the middle. The extra linebacker also limits the overall effectiveness of a running back who now has to deal with one more guy on the field who can keep up with him. In the 4-3, the defensive linemen attack the gaps between the offensive line men and hope to intercept the running back at the line of scrimmage. As you can imagine in a 4-3 linemen get more sacks and tackles than in the 3-4 where the linebackers have to do all the playmaking.
(3) In the 4-3 the primary pass rusher (usually attacking the left tackle) is a defensive end (DE) who mixes speed and strength to attack a quarterback. In the 3-4 the same pass rusher is usually a larger linebacker who uses the same mix of speed and strength to press the quarterback but starts the play in an upright position.
Everything on the football field is about trade offs. Abstractly, trade off being made is that the the 4-3 makes it easier to get to the QB vs. the 3-4 which improves the chances to stop the run. But realistically it will always come down to personnel. The Giants in the 80s ran a 3-4 but you could not tell because one of their linebackers was Lawrence Taylor and his only responsibility was to hit QBs. Around the same time, Buddy Ryan introduced the 46 defense, so named for his Free Safety who basically lined up with the linebackers in a base 4-3, basically putting another blue bubble in that circle. Pretty revolutionary really.
(2)Can't players be flexible enough to play both defenses, and switch up as the game conditions dictate?
Sometimes but not often. The players used in each scenario actually have different physical attributes.
You will notice in the pictures above, below the position I have listed a series of weights. For the offensive line, I used the Philadelphia Eagles in both diagrams. The Eagles are currently the biggest in the league. It should be pointed out that the Eagle tackles, Tre Thomas and John Runyan are both 6ft7. To put it plainly they are big. To be dramatic I will call them an "immovable object"
So we need an irresistible force, right?
For my protypical 4-3 defense, I used one of the better defenses in the league, the NY Giants. You will look at their weights and scratch your head "these guys are small! How could this possibly work?" Pull out a physics text book:
Force = mass x velocity
Yes they are relatively small but they are also incredibly fast. The ends are almost as quick as linebackers and the linebackers all share above average speed. Most of their sacks come from beating larger offensive linemen off the ball and getting by them. Its pretty neat to watch.
For the 3-4, I chose the NY Jets. You will notice that the NT (Kris Jenkins) weighs 350lbs. He is the biggest man on the field. He's a pretty weird athlete. He could overpower any single lineman relatively easily, so he usually commands two defenders. His lineman also have the responsibility of attacking one on one, so they have to be close in size and strength to the offensive linemen they line up against.
It's just plain hard to ask Giant defensive linemen to ever line up in a 3-4 scenario. The linemen they have on their roster (usually around 6) are all optimized for the 4-3 scheme, trading size for speed. They just don't have any one to be a Kris Jenkins type and the opportunity cost of having one of these guys on the bench is really high and grows exponentially when a player gets hurt.
It's easier to go from a base 3-4 to a 4-3. When you do this, you ask your 3-4 linemen to play a different role than they they are accustomed to, making tackles etc. The Jets would shift periodically with mixed success. Its unclear that this provides any competitive advantage. The Giants had a better defense than the Jets in most categories.
There are exceptions. The New England Patriots start at a base 3-4, but depending on the opponent or even the game time situation they will take out the linebacker and put in another lineman and switch to a 4-3. Not every team can do this. Again this is due to personnel. Most of the Patriots linemen and linebackers are similarly sized so they trade off very little when they do this. They are also incredibly well coached.
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