For me, the most difficult were the mountain sites in Asia. I still tried to follow the contours like I would if it were a normal 2 foot contour interval, but they were 5 to 10 meter contours, LOL. Instead of leveling a cross slope on a fw by a few feet, you sometimes had to lower one side by 50 or more feet. And, if filling, the distance it took to run the slope out was substantial.
But as an example of following contours rather than just routing as if the topo wasn't there, I was called in to help on a project and managed to reduce cut and fill from over 2 Billion CM (with a B) to about 1.2 Billion, and the legislated limit was 1.6 Billion CM, from memory (it has been a while)
On more normal sites you might find in America, I think a constant slope across the property might be the most difficult, except as Ally notes, small property with odd shape. Think Olympic where you can go downhill off the first tee, but must come back up slowly (i.e., their 17th and 18th as long gradual uphill slopes, along with holes like 8 which are difficult, blind, uphill par 3's.