While it would be great if there was a simple answer to this question, the real right answer depends to a great extent on your own particular situation. There are literally dozens of steps you can take to save on your home heating and cooling costs, and which ones are most appropriate for you will have a lot to do with what you already have, how you use it and where you live.
For instance, if you have a well-insulated house but your HVAC system is more than 10 or 15 years old, investing in a new system will almost certainly save you a ton in the long run. Even if your existing system is working well, the newer systems available are simply so much more energy efficient that having one will cut your monthly bills dramatically.
Plus, you will be replacing your system relatively soon anyway if it is that old, so you might as well start saving now on your heating and cooling costs. However, even the best heating and cooling system on the market will not save you that much money if you do not have a properly insulated and sealed house.
Insulation keeps the warm air in during the winter, and it also keeps colder air from seeping in. In the summer, it works the other way around, keeping in the air you are paying to cool and keeping out the hotter outside air. If you do not have thorough insulation or if it is too old, that temperature controlled air that you are paying for will be leaking out and unwanted outdoor air will be finding its way in. You will pay much more than necessary to keep the indoor temperature comfortable as a result.
If you have both good insulation and an energy efficient HVAC system, your thermostat might be the place to look when you want to try and cut your energy costs. A programmable or wireless thermostat might be just the ticket you need to cut back even more on your energy bills because of the added control it gives you to more precisely regulate the temperature inside your home.
Particularly if you have a large house, you might even consider having a zone control system put in so that you can set different temperatures for different areas of the house. After all, there is no need to be paying to regulate the temperature in a part of the house that is unoccupied.