What is the most isolated and difficult destination you have visited?

I would say either the Osa Peninsula in Costa Rica, or Coober Pedy Australia. They both are very difficult to get to and take many different forms of transportation, pedy was truly in the middle of no were, on a Mars landscape. But the osa is the winner! It was hard to find people even if you wanted to!

Twin Lakes and Telaquana in Lake Clark National Park and Preserve. Three plane flights (minimum), VERY "changing" weather, and 6,000,000 acres of wilderness, AND you are NOT at the top of the food chain. But, it is stunningly beautiful, and very likely you will have it all to yourself. Very little public traffic in this park at the moment and limited services, confined to the one small town, Port Alsworth. Small plane flight service into the park launches from here. If you want to see what this place looks like, follow my current blog,..we are flying over/through the park: http://rbtglennketchum.blogspot.com/2014/10/weekly-post-no-pebble-mine-pictures.html

This would have to be Qaanaaq Greenland.  We had to do a medivac of the Inuits there on a Dehavilland Bush plane in 70 mph winds.  It took a 767 to Sonndestrom, a Bush plane and a Helicopter to go...  Very desolate in northern Greenland, but eerie at the same time, if you have the chance to go I would do it.  

When we were in Laos we took a river trip from Louangphabang to Muang Ngoy which is only reachable by boat (actually two boats or a transport and a boat).  The view from the restaurant over the river there is spectacular (and one meets THE most interesting travelers there). There are no motorized vehicles.  The temple drums are played some nights and  waking one  to pure enchantment.  Our idea of heaven if you are a traveler and not a tourist as the accommodations are rustic.

I suppose Jos Plateau, Nigeria. It's spectacularly wild and beautiful, for many decades a favorite vacation spot for British expatriates. I was there a long time ago; in recent times, it's been the scene of horrific sectarian violence, but that's true of a number areas in Northern Nigeria. It's very sad.

This summer I was cycling from Teresina to Serra Talhada in Northeast Brazil and during that trip I only met one person who could speak any english (I speak portuguese so I was not lonlely).

At one Hotel I stayed the front desk receptionist had never seen a passport in his life as I was the first foreign client who had ever stayed at the hotel in the 5 years it had been there.

The hotel was mainly used by local truck drivers who were going through this part of Brazil that hardly ever sees foreign visitors and from what I know I was the first non brazilien to ever cycle that route.

I'm not terribly experienced when it comes to travel, but for me it was Lipari. Talk about a LONG ferry ride. I believe it was a seven-hour boat trip from Lipari to Naples, just to put into perspective how long it takes to get there.

However, it was one of my favorite places when visiting Italy. If you're in Palermo and go to Lipari, it's not that bad of a hike. Being in the middle of the sea is heavenly. :)