Basic DOE Question

I have a question regarding DOE. 

DOE defined as: Conducting and analyzing controlled tests to evaluate the factors that control the value of a parameter or group of parameters.

When designing a DOE, the engineers, process experts decide which factors should be changed, or varied and what responses should be monitored.   My question is how does a DOE team know they are including all the necessary factors and responses?  Isn't it possible that critical factors could be missed or the incorrect response selected?  I realize the engineers and process experts are using their experience and knowledge, but is guesswork involved too? 

If this happens, it's possible a tremendous amount of time and effort would be wasted.  And isn't it possible the true factors or responses that are sought might never be found?  I worry something critical or important might be left out because of the guessing about factors.

I'm just a little confused, but not doubting the usefulness of DOE.  Any thoughts are appreciated.