A model can be significant and explain a lot of variability and still exhibit lack of fit. For example, the model may be missing an important term, as shown in the attached simple example.
A significant lack of fit usually indicates that the model form is not correct and usually indicates that there is a curvilinear relationship. Residual plots are the best and easiest tool to use to try and determine why there is a lack of fit. A good residual plot will show random scatter. Any pattern will indicate a systematic problem with your chosen model. For my simple example, here is a residual plot (there is more than one residual plot, so look at all of them to help determine the problem with your model).
There is an obvious pattern here indicating that I need a quadratic term in the model to estimate the curvature. I THINK this is a problem with your model as well, but the residual plots should help you.
Dan Obermiller