If the play is a running play, the job of the defensive linemen is just a little different. The DEs will still run forwards towards the quarterback, but now they are supposed to keep the running back from getting past them. In a perfect world, one of the DEs would tackle the running back in the backfield for a loss of yards. In any case, they want to make sure the running back has to run towards the center of the field where there are two DTs and three LBs just waiting to make him a very unhappy running back. The job of the DTs in a running play is to clog up the center of the field so that the running back has nowhere to go. In a perfect world, one of the DTs would tackle him. If all four of your down linemen miss the running back, they still should have kept him in the middle of the field, and slowed him down as he picked his way through all the very large bodies fighting over him. This gives your linebackers lots of time to track him down and do him great bodily harm.
If you can manage to get two large, strong DTs and two fast and effective DEs on your team, these four guys all by themselves will make life very unpleasent for the quarterback. They will make certain that he does not have enough unharassed time to make a long pass for the endzone; the quarterback will have only about two seconds to read the defense and get rid of the ball. This will pretty much guarantee that the only available receivers are within about ten yards of the line of scrimmage. This leaves seven other guys on your defense, three linebackers and four defensive backs, to cover the various receivers. A 4-3 defense with four good down linemen is very good at stopping the pass.
On the other hand, you can see in the diagram above that the 4-3 defense leaves an A, B, and C gap uncovered by a lineman. It's up to the three linebackers to cover these gaps, and also be ready for a running back who manages to get outside of one of the DEs. The 4-3 defense is not quite as good at stopping the run as we can imagine.
In the fall when the weather is nice, teams like to pass a lot, and the 4-3 defense is pretty good at limiting these passes. But in the winter when the weather turns cold, the wind comes up, and the football is cold and hard as a rock, teams like to run the ball. This can cause problems for a 4-3 defense.
If you cannot find four good down linemen, you're in trouble. You must find a way to disrupt the quarterback, so pretty soon you'll try what is called "blitzing," after the blitzkrieg strategy used very effectively by Hitler against the allied armies. In a blitz you will have one or two other players, linebackers or safeties most frequently, join with the down linemen in rushing in to get the quarterback. However, this is one or two fewer people to cover the receivers. A good quarterback will quickly find the receiver who is not covered because of the blitz and get the ball to him. Most often this receiver will be directly behind the blitzing defender, running into the area that the blitzer just left. If the quarterback sees a blitz coming, his first instinct is to throw the ball quickly right over the blitzer's head into the unprotected area. Because of this, it's common in football games to hear the phrase "Live by the blitz, die by the blitz." When a blitz works, the quarterback gets sacked and the offense looses ten or more yards. When the blitz fails, the quarterback often gets the ball to an uncovered receiver who then runs for a twenty yard or more gain.
It's very difficult to find two good, fast, 290 pound defensive ends to make your 4-3 work. If you do find them, they're worth $5m to $12M per year each. If you don't find them, you're in for a very long season of living and dying by the blitz. The best defenses have these guys and do very little blitzing.
Above is shown the "4-3 over" defensive alignment. The nose tack is lined up on the weak side of the center, and the 3 technique is lined up on the strong side between the guard and tackle. The defense is putting their power straight against the offensive line power. There's also a "4-3 under" alignment, also shown above. If the nose tackle moves over to the strong side of the center and the 3-technique moves to the outside shoulder of the weak side guard, we say they are in an "under" alignment. Now the strength of the defensive line is aimed at the weaker side of the offensive line. The "over" alignment is perhaps a bit better against the run, and the "under" alignment is perhaps a bit better against the pass. In the "under" alignment you have three defensive linemen facing the three weakside offensive linemen, so neither the 3-technique nor the defensive end can be double- teamed.