Chicago, IL to Port Isabel.

Actually Memphis is not that bad. Once you cross the bridge you pretty much go around the busy part. The worst place if you go that way is Baton Rouge. Going west thru Baton Rouge is not too bad, but going East the traffic gets jammed up going over the bridge. If you hit it in the afternoon going east it will take anywhere from a hour or longer to get over the bridge. I am looking for a better way but have not found any yet.

Actually, that is a good way to go, traindriver, and it avoids most major cities, except for Memphis.

I don't know how you can avoid all big cities, wish I could figure that one out. I go I-57 to I-55 to I-12 to I-10 to Winnie, Texas. At Winnie I take Rte 89 (I think) down the Bolivar Penisula and take the free ferry across to Galveston Island. Stay on beach blvd right thru Galveston down to Surfside. At surfside take rte 36 over to rte 35. Then rte 35 to Corpus Christie and rte 77. Rte 77 to south of Harlingen to rte 100 and 100 to Port Isable and South Padre island. Not the shortest way but after you get to Winnie, the rest of the trip is a nice easy drive and a fun way to go. OR you can go 57 to 55 to 40 to 30 to Texarcana. At Texarcana take 59 to 79 to 77 to Rte 100 to Port Isabelle. After you leave Texarcana , good roads, not much traffic, no big cities. That's how I go YMMV.

Based on the frequency of bad roads wherever we go I'd suggest Southwest Airlines perhaps out of Milwaukee.

Wife and I left that dreaded state of Illinois 3 years ago to begin our full time adventures. We eventually ended up in Port Aransas TX which is just north of North Padre island on mustang island. Never made it down to south Padre where you are going but heard good things. Anyway as far as the journey I just drove back up here to the Midwest and currently in Michigan but heading back through the suburbs of Chicago in a month or so. I would catch I57 heading south at some point and avoid St Louis and reconnect with 55 into Arkansas to I40 but I will say that the stretch of road between west Memphis and little rock is horrible. It was bad 3 years ago when I was heading south and still bad 2 months ago coming back up. Once past little rock it really is a nice drive into Texarkana. Degray lake state park is in there and really nice camping. Bypassing Dallas to the south onto the infamous 35 corridor is a serious road from Hillsboro through San Antonio. The construction is everywhere and narrow lanes and the combination of high speed limits and truckers that will let you know they own the road. I pull a 39' tt and a few times almost got clipped by some big rigs passing in a construction zone with shifting lanes so had quite a few white knuckle moments. You're good to go once past San Antonio and someone above mentioned that bypass toll road but I'm not familiar with it however I know people like it. As far as taking the back roads through Texas one thing to consider is that many of those roads are two lanes with high speed semi truck traffic either coming at you or riding you're bumper because you're not driving 75. A lot of oil field truck traffic and some are rough so you have to decide where you are more comfortable. Sorry for the essay

You'll probably get good advice on various snippets of the road south. Here is my contribution. AVOID Austin Texas. It's a great town if you plan to spend time there but if the plan is to move on through, note that the environmentalists have done a great job over the last 30 years making sure I-35 stays narrow and clogged. Spend the tolls necessary to do the 130 bypass at Georgetown around Austin to the East down to Seguin. You can then jog over to San Antonio and skirt the Eastern flank of SA on Loop 1604. You have 2 choices south of San Antonio, 281 or 77. It's been a while, but I think 77 through Kingsville is the better route. Watch out for Javelinas.

Where is Island Lake? Not a household name, not even for some who live 20 yrs in Chicago.

Port Isabel is better known - that's the south tip of Texas.