I just realized that the first time that the Doctor (then, in his tenth incarnation) met River Song, it was the last time River Song will ever see him as she sacrificed her life to save the Doctor, Donna, and Mr. Lux (The Silence in the Library). It dawned on me when River mentioned in The Impossible Astronaut that they travel in opposite directions.
“Trouble is, it’s all back to front. My past is his future. We’re travelling in opposite directions. Every time we meet I know him more, he knows me less. I live for the days when I see him. But I know that every time I do, he’ll be one step further away. The day’s coming when I’ll look into that man’s eyes—my Doctor—and he won’t have the faintest idea who I am. And I think it’s going to kill me.”
And this happened in the The Silence in the Library, where we first met River Song, where she died.
WONDERLOST 