The first question, the oldest question, the question that must never be answered that's hidden in plain sight, is "Doctor who?", a question that the Doctor has been running from his entire life, as well as being the running gag of the series starting with the first episode "An Unearthly Child" back in 1963. It's strongly implied that this question is the reason the Silence are at war with the Doctor: the only way to ensure without a doubt that he doesn't answer it is to 'silence' him (to kill him).
In "The Wedding of River Song", the Doctor asks Dorium Maldovar about why the Silence want him dead. Dorium says: "On the fields of Trenzalore, at the fall of the Eleventh, when no living creature could speak falsely or fail to answer, a question will be asked. A question that must never be answered." When the Doctor asks what that has to do with him, Dorium tells him: "The first question, the oldest question in the universe, hidden in plain sight". At the end of the episode, Dorium finally reveals: "The first question! The question that must never be answered, hidden in plain sight. The question you've been running from all your life. Doctor who? Doctor who? Doc-tor who!"