Why is there no handle on the hatch? Why was it sealed?
We know about the "Quarantine" on the inside, and we know SOME stuff about the Incident in 1977 on the spot where it now sits. But we don't know enough.

Who is the "him" that Desmond was expecting?
Was it just his hoped-for replacment? Was he expecting a specific someone? Why did Dharma never send a replacment, if, as we know, they continued to send food drops?

Kate's horse that represented Wayne -- really there (Sawyer saw it), vision (perhaps granted by Jacob?), Smokey?
How'd it get there?

The old-timey radio broadcast Sayid and Hurley heard - was it local, from New Otherton? Does the "D" in the station name DXR perhaps stand for Dharma? Or have they picked up a signal from an earlier time?
Does it matter anymore? Was the suggestion of this idea just to put in our heads that there were TIME issues coming into play in the overarching story?

Is there any secret to what can be learned by the blast door map?
Or was is just something for obsessive fans to obsess over / have fun with? That's what I'm going with.

Why was Desmond physically okay (though he could glimpse the future), but not a shred of his clothes survived the hatch implosion? Conversely, why did Juliet die (though she could glimpse... what? The Side-Verse?), and all her clothes remained intact?
Mostly, this is just me calling "sexism" for making us suffer a naked Desmond but not a naked Juliet. How dare they.

At Eko's funeral, Locke says, "I'd like to think you died for a reason, Mr. Eko. Just hope it's not too long before we find out what the heck it might be."
Still waiting. Was there purpose in Eko's death? I'm drawing a blank. I mean, a second after the eulogy Locke spied the message on the Jesus Stick that said "Lift up your eyes and look north. John 3:05," but surely it didn't take Eko's death for Locke to receive this clue.

What's the meaning of "God loves you as he loved Jacob?" from the Room 23 film?
The Others don't seem particularly religious, but this sounds like religious propaganda for sure. It also indicates that Jacob and God are NOT the same entity, but that God loves Jacob... even though God can't see this island? O...k...

Dharma survived on that island from at least the early 70s until 1992. At least 20 years. Why didn't the Hostiles purge them before then?
Why wait until Ben was 28, as opposed to 18 or any other age? Why even let Dharma build there in the first place?

Why does Cabin Jacob seem to look, sound, and act so different from Season Five/Six Jacob?
Is it because he was an imprisoned spirit now set free (at some point the circle of ash gets disturbed - did this let him out? Is this the "help" he was asking Locke for?)? Or is it that a different actor was playing him? Or the show hadn't decided what kind of character he would be? Why did Jacob ever live at the cabin (if indeed he did at all) when he seemed perfectly content in his statue?

Why doesn't light "scatter right" (according to Faraday) on the island?

Who is "R.G." from the inscription in Naomi's bracelet?
A few of my favorite theories are that the complete inscription could be an anagram or - and I prefer this one - it could be the identity of another that remains hidden thus far, perhaps The Economist.
Related question: Who is The Economist? Widmore, perhaps?

If Widmore didn't leave the island until he was forced off already well into maturity, how did he amass such vast wealth and importance?
Details, details...

Why does Pierre Chang bother with candle-based aliases on the orientation videos?
It's not like he's a mysterious unknown person to the folks in the DI - he's all around the compound, living with them, overseeing things, etc. They KNOW he's Dr. Chang, man. What gives?
Oversight. They were trying to be too cool with this, I think.