On launching Mathematica (22.214.171.124) on macOS 10.13.4 I get a warning that it is "not optimized" for High Sierra. Is this a known issue being addressed?
This message is a warning delivered by High Sierra that the application you're running is a 32-bit application. In our case, it's specifically referring to the Mathematica front end, which is not only 32-bit, but also still running against the legacy Carbon APIs for accessing the windowing system.
The Mathematica bundle also contains a small number of other 32-bit binaries, but the kernel is fully 64-bit, and has been since even before macOS could support 64-bit GUI applications (since the kernel is not, in fact, a GUI application).
Based upon what we know about how High Sierra delivers this warning, you should receive it once only for any given app bundle.
We're actively developing a 64-bit Cocoa version of the front end, as well as ports of other binaries which remain unported. I'm not ready to suggest a date when we'll release this, but I'm quite confident it'll be sometime this calendar year.
Update: Version 12.0 and later releases are fully 64-bit, and the v12 front end is a completely native 64-bit Cocoa app. Furthermore, version 12 (the latest version as of this writing) has been tested with and is fully supported for macOS 10.15 (Catalina).