For me, after fixing so many computers over the years I have been able to find infections manually most of the time.
But the tools I run are malwarebytes anti rootkit, tdsskiller and if the system still seems infected I use combofix as the last one.
Other techs and people run other tools, and that is ok. While one program might catch something now they may not catch something new down the road. Now scanner I have ever seen has ever been 100%. So running a few different ones is a good idea to cover all the bases
I have also lately been seeing some new types of infections not getting flagged by anything. I have had users call me saying they have pop ups happening and when I check the system it is clean, and the last 3 times it has turned out to be add ins in firefox or chrome or IE that a crap program installed that was doing it. So instead of it being a program on the system causing the pop ups it was a plug in in the browsers. I removed them and the pop ups went away.
So the game is always changing, while one technique might work now doesn't mean it will work down the road, so you have to learn how to keep your eyes open to things that dont appear normal.
But a lot of the tools out there are meant to help with this. But they are only as good as their current builds are. While a program may rock now doesnt it mean it will rock later and it goes back and fourth like that.
But once I know a feel fine that a system is clean but things are broken I then run my Windows Repair tool. And as a last case I do a reinstall of Windows instead of wasting time if a system is to far gone.
Shane