Regardless of how much distance you hope to cover, you should have some idea of how you will get from one place to another. Transportation is a significant part of your travel budget, so planning the best route is important in saving you not only time, but also money. Everyone has their own strategy to plan out their trip, but this approach has worked for us many times.
Find the cheapest flight into the region. This involves looking at the online flight booking websites for a variety of major hub cities over a range of dates. Look at the capitals and largest cities of the more developed countries in the region. Also consider regional airlines that you may be unfamiliar to you. Discount carriers often have more affordable flights, but they offer slightly less flexibility, or may fly into a less convenient airport that is located outside of town. They often have inconvenient layovers, or additional fees for luggage or seat selection. If you choose a discount airline, make sure you understand the full cost of your travel, including getting to and from the airport. Also consider what time your flights depart and arrive. If you arrive in the middle of the night you may not be able to take the subway or public transportation. Taxis or alternative travel options are more expensive, so consider this when you book your plane ticket.
This might be time consuming, but flights tend to be the most expensive part of a long trip. Once you have a "starting city" set by your flight, you'll know where to begin.
Pick an "ending city" to the region. Again, this will likely be determined by your flights (or it could be determined by ferries or other land transportation). It may be the same as your starting city, and that's ok because you could just do a big loop through the region. If it does not make sense geographically to make a loop then it is probably cheaper to fly home from a different city than you arrive in. Before booking your tickets home though, look at regional airlines and see how much it would cost to fly back to your starting city. If the price of this ticket is cheaper than an international open-jaw ticket then this may be your best option. Once you have a beginning and an end, you should also have a set amount of time in between. This may be determined by the dates of your flights or other factors. If you're looking at a large region encompassing multiple countries, then hopefully you have several months or more.
Pick some major cities and/or sights in the region, and draw some logical lines on the map. Connect the dots, as they say. In your guidebook, check out the transportation section for each of these places and find out if you can take buses or trains to each of the other places. Consider travel times and connections. If you don't want to spend that length of time on a bus, or you don't want to travel through the night, then look for ways to divide up the trip. You should also see if you can get transportation to smaller places in between. If you're traveling to a less developed country then it is best not to look at travel distance. Road quality can vary dramatically. Instead, refer to your guide book for travel times and allow for unexpected delays. In many situations, just because two places are close in distance does not mean that the travel time is shortest. The amount of time you have in your schedule will dictate the number of places to visit and the length of time you stay there.
Make a rough schedule on paper of the approximate dates in each place and the method of transportation to get from town to town. Remember rule number one: stay flexible. Do not commit to anything, and do not make reservations anywhere, perhaps with the exception of a hotel the first few nights after you land in your starting city. Remember that travel delays happen, regardless of how prepared you think you are. Make sure you have enough time built into your schedule to allow for unexpected situations.
And that's it. It sounds easy, because it is. However, linking cities by buses or trains can sometimes be difficult. Bus and train routes and schedules change. Travel times are inconsistent. Sometimes the quality and thoroughness of your guidebook can determine this. It's often easier to learn about transportation once you get there. (Remember the rule about being flexible!)