When running a point-in-polygon operation, is it valid to run that with polygon features in straight up WGS84 and a point in lat/lng, or should both be projected into a non degree based coordinate system?
It is entirely valid, but it may not produce the results you expect in any Cartesian coordinate space. So it isn't a problem with degrees or WGS84, but rather the mapping from the ellipsoid to a plane.
If the polygon is very large, the mapping of the curved surface on the ellipsoid to the plane can produce some artifacts where a point looks like it would be just inside (or outside) the polygon, but isn't quite. That can also be an issue if some of the polygons cross the anti-meridian (the -180/180 part). If those might be an issue for your data, and you can handle the performance impact, consider something like a PostGIS geography approach.