My first choice for energy efficiency, as well as overall comfort in air conditioning options, would be to install a central air conditioning system. Central air systems can be zoned so they will only cool one floor of the home and not both. However, you certainly should plan on both and discuss that with your contractor as it may be less costly to install some of the ducting to get ready for cooling the second floor at some point in the future.
Another option might be to install a through-the-wall air conditioning unit. Many of the larger air conditioning units are available with wall mounted sleeves. To install, you'd need to cut a hole in the exterior wall and frame it out the same way you'd frame an opening for a window or door. It is very important to do this correctly, as you will be impacting the structural integrity of the house. Also, this type of system will very likely cause a heat loss in the winter, as it is very difficult to seal it to prevent cold air leaking in.
A better air conditioning option, which cost-wise will be in between the cost of a central system and a through-the-wall mounted portable, might be a ductless split system. I have Fujitsu system like this in my office and it works extremely well as a supplement to my central system, which doesn't fully extend into the office space. With ductless air conditioning, you have a wall blower that hangs on the inside wall of your home. This is connected via a refrigerant line to a small compressor which sits outside, just like a central system. The compressor supplies chilled refrigerant to the blower inside, which circulates the cooled air.
Given the above air conditioning options, my choice would be (1) central; (2) ductless; and (3) through-the-wall.
Regardless of what you ultimately decide with the air conditioning options, you should be certain to choose the most energy efficient unit possible. Energy Star has an excellent new program called Cool Your World With Energy Star @ Home that can help you understand cooling efficiency and options.