Everything changes based on the defensive look... receivers and QBs need to be on the same page with respect to the read they're getting on the defense. Man vs zone, how big is the cushion from the CB, is there safety help, is there LB help, are we reading blitz, cover-2 vs cover-3... it's a complicated set of reads and it takes time to get it down and it's normal for there to be some mis-reads during a game, whether it be by the QB or the WR or both. Ideally a QB reads the defense pre-snap and focuses on one defender at the snap... if he moves this way I go to the X, if he moves the other way I go to the Z.
So it's not as easy as simply "not knowing their assignments."
Still a huge bummer though.