“Qui est-ce ?” when speaking to somebody and indicating someone means you want information on this someone.

“Qui est-ce qui parle ?” is the exact same question except that you indicate this someone by the fact that he is speaking right now.

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.

FR: qu’est-ce qui / qu’est-ce que / qui est-ce qui / qui est-ce que | WordReference Forums

The first que/qui tells you whether the answer to your question will be a person (qui) or an thing (que).
The second que/qui tells you whether the answer to your question will be the subject or the object.

QUI
SUJET: Qui est-ce qui mange? Il mange.
OBJECT: Qui est-ce que vous aimez? J’aime James.

QUE
SUJET: Qu’est-ce qui te fait mal? Mon dos me fait mal.
OBJET: Qu’est-ce que vous voulez? Je veux un chaton.

When you have Qui…qui or Que…que, you can omit the est-ce part:

Qui est-ce qui mange? → Qui mange?
Qu’est-ce que vous voulez? → Que voulez-vous?