Hi,
If you mean ModalPopup from AjaxToolkit, then various unusual things may happen. Particularly it sets fixed positions for elements and huge zIndexes. That is quite a challenge for an application if it uses elements on page with relative (like webgrid) or absolute positions, or if application uses its own external popups with smaller zIndexes.
If it is that ModalPopupExtender, then since source codes are available and you may fix and recompile them, then you may consider to reduce/remove zIndexes and maybe replace fixed positions by absolute.