There are some decent deals to be had, particularly when flight and hotel packages are considered. I regularly use Expedia when travelling mid-week to the USA, to avoid the penalty for not staying for a Saturday night.
Don’t forget that Expedia offer Nectar points on all purchases, which may offset the potential loss of hotel brand loyalty points on these stays.
One slightly-obvious tip: It is always sensible to check the cost of rooms on Expedia with the same room booked direct with the hotel. These days many hotels price match against the online agents, and when checking out this deal I saw that both the May Fair and the Four Seasons hotels in London were matching the Expedia prices head-on.