Essentially, they enable you to drive better locomotives, longer trains etc, thus increasing your potential profits.

But there are 2 downsides:

• Each license costs money.
  
• Almost every license you buy also impacts on your insurance copay.

Essentially, the more licenses you have, the less your insurance will pitch in when it's time to pay those fees for maintenance, fuel, damage etc. In other words, they decrease your potential profits, permanently (*).
So it is only prudent to choose carefully which licenses you buy, especially early in the game.
Hence this guide.


(*) The good news here is, over time and after completing a few jobs, the "insurance tolerance" increases, too. So it will take progressively longer before the insurance copay is due, which in turn translates to more net profits again. Just try to make the best possible use of the insurance tolerance.

DE2 (provided in the game's tutorial)
FH (provided in the game's tutorial)
---
SH (Shunting)
LONG I (Train Length 1)
CCUR I (Concurrent Orders 1)
LH (Logistical Haul)
---
LONG II (TrainLength 2)
DH4 (or, if you prefer a steamer, S060)

The idea is to do some shunting (since you are licensed for a shunter), and maybe some lightweight (preferably downhill) freight hauls.
The Logistical Haul license is really useful because those trains aren't loaded - they are lightweight and a shunter can handle them.
By the end of this roadmap, with the DH4 and Long II, you should be well-equipped to make decent profits and eventually move on to the bigger and more difficult things.

Hazardous Materials tend to come in tankers. Those are heavy, even when empty. Not recommended until you have a DE6 (or similar) license.

Military licenses are pricy and offer only a few destinations on the map. I'd consider them an end-game thing.

The S060 is cheaper than the DH4, but it has less traction and needs maintenance more often (water refill), and that will trigger your insurance copay more often than the DH4, at least until you have the Manual Service license. Just something to keep in mind.

The Locomotive Remote[derailvalley.fandom.com] may be worth its price if you do a lot of shunting.
It also comes in handy when you have to back a train in reverse for part of the route.
Hardly a day goes by when I don't use it.

Derail Valley is great.
But there are some "Quality of Life" gizmos you may want:


Remote Dispatch[www.nexusmods.com]
Allows you to remotely set switches along your route, find your jobs' trains more easily in crowded yards, and more.
The vanilla way to do these things tends to be a little annoying, spoiling much of the fun in my opinion.

DE6 Remote Control Support[www.nexusmods.com]
Honestly, I don't see why the DE6 RC support has even been removed.
The RC is pricy enough, why wouldn't it work with the DE6 the way it used to?

HUD improvements
There are various other mods - particularly the ones that help you better judge the track grade and upcoming speed limits ahead are helpful for me. DV tends to throw surprises at ya that sometimes can be tricky to detect early enough to manage power / brakes accordingly.

Here's a nice video on how to install mods:
(Credit goes to Niko the cakefox)