People get really grumpy when they realize you're giving them directions for how to go to the store and buy a GPS.
Andrey Kolmogorov was a mathematician who worked, among other things, on defining computational complexity. Roughly speaking, the Kolmogorov complexity of a string (of bits, words, symbols, etc.) is the shortest description that allows an accurate reconstruction — or, in some variants, the length of the smallest program which will output the original string.
Cueball's method of giving directions is very reminiscent of Kolmogorov's method of determining complexity. However, it is unlikely they know all the presidents, nor can calculate prime numbers in their heads, and so will have trouble with certain parts. These directions may have minimal Kolmogorov complexity, but they are non-intuitive and are likely not the shortest or quickest way to get there, considering that they consist mostly of left turns.
For most routes the shortest algorithm will very likely be based on some Maze-solving algorithm which is guaranteed to eventually visit every place and follow it until you reach your destination. This might take a very long time (for example, it is possible that the algorithm will have you travel through all of Canada first for a trip between two US cities).
This is not the first time Cueball has had difficulties with directions, and here we see he hates giving directions as much as he hates receiving them.
The joke in the title text is that Cueball just sent his friend to a store to buy a GPS device to give him the correct directions. (By the time this comic was published, GPS-enabled smartphones had already largely displaced dedicated GPS devices,[1] but Cueball could be talking to a person who does not wish to own a smartphone.)
The superfluousness of giving directions as opposed to using a GPS is the subject of 783: I Don't Want Directions.