We have tried trains, planes, and automobiles, and by far the most pleasant trip was on the train. You don't have to deal with getting through security, the seats are more roomy, the windows are bigger, and there is room to roam and explore when the kids get restless.
Pack as many snacks and small activities as you can carry.
Kids have short attention spans and run through activities quickly, plus you never know when you are going to hit a traffic jam or delayed flight. Portable DVD players can be a lifesaver, and some of our other favorites are books of all kinds (reading, coloring, sticker), small etch-a-sketches, and handheld computer games. It is always helpful to have some new toys that they haven't seen before.
If you fly...
Investigate seating arrangements and get preassigned seats if possible.
There are rules about how many lap children can be in any given row to make sure there are adequate oxygen masks, so depending on the plane and whether you have booked separate seats for the children, you may need to split up. It is much nicer to know this in advance and to be able to strategize accordingly.
Consider buying separate seats for babies/toddlers.
It is hard to pass up the free lap travel for children under 2, and we have never actually done it, but it is worth at least considering getting seats for the kids, especially for long flights, so that everyone can have their own space.
Look for family security lines.
Getting through security with 2 small children, a stroller, diaper bag, carry-ons, etc is a nightmare. It gives me hives even thinking about it. Some airports have lines dedicated to families. Seek these out and use them, even if they have a longer line. Everyone will be infinitely more patient and you will be able to avoid the looks of death from fellow travelers as they wait for you to struggle through security.
Check the stroller at the gate.
You can end up having to walk miles in the airport, so having the stroller up until you get on the plane - and immediately upon arrival - is really helpful. Even if you don't use it for the kids, you can use it to cart your bags around.
Escalators and moving sidewalks can provide hours of airport entertainment for small children.
This allows you to save your other activities for the flight.