No one is perfect but a post signed "washu" is a pretty good reference, especially when it comes to storage.
I don't use ReadyBoost and I don't know the details. If it indeed caches only random reads as washu says, it's not going to be very useful if you have lots of spare RAM (on the other hand, if you've got an application that uses that RAM...).
a never ending headache with older games, smaller programs, and internet updates that couldn't find what they were looking for. I even went into %path variables and fixed them to point where I wanted.
There is absolutely on reason you'd have such problems if you only used your slower drives for large data files like movies. You wouldn't have had these issues then and you wouldn't have them now.
But if you have games so big they wouldn't fit on a reasonably-sized SSD, they could theoretically give you trouble if you wanted to install them on another drive. It would be very sloppy on the designer's part but it's possible.
Another possible problem you might have is stuff like games looking for their CD/DVD at the wrong drive letter. But this can happen even if you add an empty drive and put nothing on it. Worst case, you can fix the problem by reinstalling the program.
For what that's worth, it's possible integrate several drives in your "C" drives but I think that would be unnecessarily complicated.
Seeing that, at least on Newegg, the USB3 64GB flash drives cost the same as the 64GB SATA3 SSDs, I do wonder what the performance difference would be. The USB devices report lower "Read Speed" and "Write Speed" performance than the SSDs, but I have no idea how much that matters. Both are as fast or faster than my HDD tested.
You don't need USB3 for ReadyBoost. Just pick a reputable brand and avoid the bottom-of-the-barrel models. Specs are useless. Almost all Flash drives are much faster at random access than hard drives.
That said, I believe washu: don't bother. I was assuming ReadyBoost would cache all reads.