Your comic completists will sit and read every issue of their favorite book(s) chronologically, but, especially in the case of your long-runners, your more discriminating comic fans look for just stories featuring their favorite character, or titles/issues covering a particular series arc. So it all comes down to your own preference, I suppose.
@NostradamusTheSeer brings up a good topic of discussion. AT&F is a long running comic OFFICIALLY now. They have over 900 "episodes" as they call it. Each page is a "episode" even though they have some storylines that span several "episodes" in a row.
It's a series I feel you can pick up and read any episode and laugh, but at the same time, it's a series that sort of does require you to start from the beginning, understand all the storylines and arcs, and learn about the characters to fully grasp and enjoy the jokes and stories it tells. I don't know if one can just skip episodes and really just read the one's with their favorite characters in it. You kind of need to read it all to really learn these characters. You love to hate some and learn to love others. It's fun watching them grow and evolve over time.
Also... floating timeline. They have seasonal episodes for Christmas and Halloween and other holidays, we even see seasons. But it seems like no-pony ages. Everyone remains the same age. Is the series actually taking place in a really short time span (minus the holidays) or are the holiday episodes just a unique non-canon thing? It's kind of weird and fun to overthink this stuff. Clearly there is a time line because things progress in the series, but is it really in the span of years? The Simpsons does similar stuff to this. Many holiday episodes, but no one ages. It's like AT&F is set in a period of time, where things to advance, but the characters remain ageless, or the same age.
Maybe a comic-titian with a better pedigree can explain the world of AT&F better or comics in general.