These are what I think might happen. Feel free to add your own.
That the CMC will one day get their cutie marks.(and I think one by one so that when one of them gets their cutie mark, they can help the other get theirs. It also might lethen the CMC story ark).
That the rainbow coloured thread that rarity was given and the wonderbolt badge that rainbow was given will help them get their keys to the mysterious box.
That the real shadow pony will appear.
That there will be another alicorn princess.
That there will be, inside the mysterious box, new elements of harmony.
That in the upcoming episode twilight time, twily will get her special item (a book, or maybe a quill or even a new crown).
That the diaries will become very important soon, as part of the season 4 story.
That there will be a fluttershy episode including discord.
That there will be an episode taking place in fillydelphia.
That there will be a sparity themed episode.
That the ponies pets will make a comeback.
That more background ponies will get a speaking role.
That in season 5, twily will turn Back into a unicorn for some good reason.
That there will be a episode taking place in saddle Arabia.
That babs seed will come back.
That flutterbat/flutterrage will return.
That there will be at least 1 new villan.
That winter wrap, running of the leaves, hearts and hooves day and hearths warming eve will occur again.
That trixie shall return.
That pinkie shall break another fourth wall.
That we will learn more about each of mane sixes histories.
That more relationships shall be learnt about (I'd love it if derpy was related to dash!).
That's all I have for now, but fell free to add your predictions. Bye! ;)