Qui est-ce ___ parle ?
What should the blank be filled with?
I am really confused about this! Is there an explanation?
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Here are example of correct uses of "qui" and "que" :
Qu'est-ce que tu en penses ? (What do you think ?)
Qui est-ce qui parle ? (Who's talking ?)
"Qu' " is the form of "que" used before a vowel, like in "qu'est-ce que ...", or in "qu'est ce qu' il en pense ?"
Sometimes the first pronoun is the same as the second one (assuming "qu' " == "que"), but it's not always the case.
When it is, you can phrase these sentence to use only one pronoun, though it's a little too formal for casual conversation :
Qu'en penses-tu ?
Qui parle ?
Edit : As Stéphane mentioned, there are other cases, when this doesn't work :
Qu'est-ce qui est rond et rouge ?
This phrasing is typical in riddles for example.
In the last sentence, we're still talking about and object, but there's a difference : "Qu'est-ce" is the subject, to the verb "être" : "Il est rond est rouge".
While in the first sentence, "Qu'est-ce" is the complement, while tu is the subject : "Qu'est-ce que tu en penses ?".
So here is the rule: qui follows the subject of the verb, while que/qu' follows the complement.
My apologies for my hasty and incorrect first answer.