First noticed this trying to get "play" in the Melodyne plugin (not so straight forward and easy, and not something I've gotten used to second nature). Then I found out I couldn't even get "PLAY" to work in Reaper at all, even on an older project without Melodyne.

I have no idea what I may have screwed up trying to "fix" other issues, or it that had anything to do with it.

Anyway, just wondering if this has occurred with anybody else and how it might be possible to resolve.

I have a paid license with Reaper. if that matters.

Hmm, never heard of this.
What theme are you using?

No idea. Whatever theme it installed to, I reckon. I haven't knowingly changed a theme.

By the way...don't spoil your 20,000 post anniversary answering a "how do I computer" question

Have you tried uninstalling/re-installing Reaper?
Since it saves songs to a different folder (by default I think) it should be pretty painless.
Just trying to help .. I know I need help often enough myself

Actually, I reinstalled the focusrite. APPARENTLY "play" was disabled when Reaper couldn't find a driver. So far, so good. Hopefully no major meltdowns until October. I'm expecting my microphone to explode or a cable to burst into flames about then.

I've had a similar problem still not resolved. I hit play and it won't play on any song file I open old or recent. I got some pop up about the sound card driver but it would close to quickly for me to read it. I even tried to recreate the pop-up while videoing the screen so I could freeze frame and read it. I updated the driver for my Behringer UMC204HD and still same problem. Finally, I disconnected UMC204HD and started using the headphone output just to keep moving forward with my song schedule.
I do take my computer to remotely work on music with the UMC204HD disconnected at times and I'll have to mess with the soundcard settings to get sound out of the headphone jack and then mess with things again to get the UMC204HD to work again.

Now, I had assumed this problem was caused by either a (Realtek High Definition Audio) soundcard conflict with the UMC204HD or a defect in the headphone out jack that detects when I plug or unplug a jack there. I have to wiggle the cable at that jack to make good connection to the headphone cable or output cable.
Since reading this post I'm thinking it might be related to that latest Reaper update but I don't really know.
Also thinking it might be a problem in the UMC204HD and I'll have to replace it but don't want that expense right now especially if I don't know exactly what's causing the problem.
For the past several days I've had the UMC204HD disconnected and so far no issues. But, I'm going to start recording audio soon and need this problem solved.
So, if anyone does know a solution I'd be greatful to have suggestions before I start spending time to figure it out.

Good luck Tobias. While I didn't get a message (at least not one I noticed), that does seem to have been the issue...failure of Reaper to locate a driver. I uninstalled my focusrite and reinstalled a driver from the Focusrite website. That *seems* to be what has fixed this, and so far still so good.

I looked over the focusrite forum and saw no mention of this. Did the same at the Reaper forum, and found no mention. BUT I didn't look hard and long at either place.

I'll leave this thread unmarked Resolved.

Sorry guys, can't help. Reaper continues to work like a charm for me with no issues. I have the Motu Audio Express.

Go to Reaper Options and make sure the settings for your UMC204HD are available as an option.
Test them.
It could have simply reset the defaults to something else.
Easily happens if you do an update with the USB device not powered up.

In Reaper it's Options - Preferences - Audio Device