It all depends on the layout size for me. At my operating club, the Paradise and Pacific, I've run up to 75 scale freight cars with either two or three powered locomotives. Usually two as the grade is minimal on the loop I run them on. The total train length was about 80'.
However, yes, there can be some operational difficulties with a train that long. the biggest is simply being vigilant to make sure that cars aren't derailing which can lead to messy crashes. I find that 25-40 cars can run for hours without a lot of concern.
Of course, I run quite bit of old Roco-Atlas, old Weaver and other lighter cars at the back of the train. While the modern offerings are so much better in terms of detail, they can make a train a lot heavier real quick.
For passenger I've run over 20 cars, but prefer to keep my trains to about 12 cars and two powered locomotives. It looks about right for that layout.
At home, it's a different story. On my modular 16x7 layout I have about 20 cars on the freight train now and an 8 car Canadian set on the other mainline track. I'll be switching those out though for shorter trains. Both trains are a little too long for that layout.
Finally, if I ever get my 2 rail layout built, I'll limit the passenger trains to about 5 cars total and the freight trains to 10 or less. That's just based on the room size I have.
Here's 47 cars operating for about 4 continuous hours from a few weeks ago in Scottsdale.