A lot of my knowledge have come from mixing with the "clever" fly fishers.
Experimenting and time on the water is the most important factors.
When you are on the water, observing and analyzing what you see is critical.
Is it a incoming or outgoing tide?
Are the fish swimming with the tide or against?
What is the wind doing?
What is the barometer doing?
Water color?
If they are not interested in a lightly weighted fly, what about a super heavy fly? (this was the biggest revelation to me. Always trying to fish as light as possible, thinking the fish would feel the weight and leave the fly very quickly. Sometimes, the heaviest fly produces the best results)
Never be afraid to change tactics.
The strangest things/colors sometimes yields amazing results. (think about the different colors in Rapalas. The bait fish don't look orange, but it is a super color)
Above is just some of the things to think about.