Okay, in general I usually put floatant on my dry flies, but not always. In the case of CDC flies you should never put floatant on the CDC. And there are times it works better for other patterns. I often fish a blue/grey quill hatch on the Poudre. I'm not really sure which bug this is, but I've found fishing a dry with no floatant seems to work better for this hatch. Basically, its like fishing a cripple and the fish like an easy meal.

Another situation is a Trico hatch. If you see lots of Tricos on the water, but no fish rising then the fish maybe taking spent tricos that have sunk below the surface. Especially if there are some some riffles.

Caddis flies can also be fished under the surface. Many caddis dive under water to lay their eggs. You can even find Diving Caddis patterns, but if you don't have one a regular dry will work also.

So if your sure you have the right dry, and its not working try fishing it drunk (i.e. without floatant).