Please run through these steps in order.

Prerequisites

Ensure you are trying to start modded by clicking "Start modded" within r2modman. Launching the game through Steam should by default provide an unmodded experience.

The game doesn't launch at all

If the game runs through Steam, this means that your Steam directory is probably incorrect in the manager settings.

The default Steam location is C:/Program Files (x86)/Steam

Note: this folder contains the Steam executable and not the game executable.

If the game is not running through Steam, please set the game directory correctly.

If your anti-virus is preventing the launch, then set an exception for r2modman.exe.

Black screen on launch

1. Select the Profile producing this problem.
2. Click on Settings -> Debugging -> Run preloader fix
3. Wait until Steam has finished validation and you're done.

The game starts but no mods are loading

Games via Steam

1. On Steam, right click the game and go to Manage -> Browse local files
2. Take note of the path.
3. In r2modman, select a profile and go to Settings -> Locations -> Change <game> directory.
4. Ensure these directories match. You won't see any files because it's a folder selection dialog. As long as it's the same path as the one in Steam, this is fine.
5. If these already match, continue to the next section, otherwise try starting modded through the manager.

Checking launch arguments

You may have overridden the launch arguments for the game at some point. Ensure to check that the launch argument box is empty by doing the following:

1. Right click on the game on Steam and go to Properties
2. At the bottom there's a box where you can type text. Ensure this is empty.

Non-Steam games

Set this to your game executable. You'll need to see how to find where your game is installed depending on how you installed it (EGS, GOG, Oculus, other).

Corrupted BepInEx installation

1. Settings -> Toggle download cache (disable it)
2. Settings -> Export profile as code
3. If you don't get an export code, this is a definite sign that it's a bad BepInEx install. You can skip straight to step 8 after re-downloading BepInEx from the Online section.
4. Settings -> Change profile
5. Import -> From code
6. Select new profile
7. Start modded
8. Toggle the download cache (enable it)

Run as admin

Running the manager as an administrator may be required if a folder isn't writable with the ordinary permissions.

Assuming this fixes the issue, a better alternative would be to move your game directory to somewhere that doesn't require the manager to be ran as an administrator.

Finally

Try restarting your PC. It's been reported to have solved the issue on numerous occasions, so it can't hurt to give it a go.

Anything else?

If you are using r2modman, ask for help in the r2modman Discord Server.

If you are using Thunderstore Mod Manager, ask for help in the Thunderstore Discord Server.

Please use the correct Discord server. Do not use both.