Is there a definite difference in the pronunciation of "è" and "e"? Will one just assume, based on sentence context, that the word is definitely "and" or definitely "is"?
Yes, there is: è is pronounced open like the E in "pet", while e (é) narrow like the one in "eight" or the A in "day".
Perché means how or why. Come means what or how. Cosa means what.
Does it matter when you use each one? How do you know when to?
The audio on this one is pretty bad - like a robot from a 1960s sci-fi movie.