I’m doing animation-heavy projects completely in Blender.
I haven’t run into any problems with Z-up vs. Y-up so far. Skinned meshes are imported into Unity with the correct orientation and animations are working fine. The local bone axes are often pretty random, but so long as animations play, ¯_(ツ)_/¯
I’m not using root motion (and the model preview does show the model on its side when in the inspector, animation tab, motion group I assign my model’s root bone to the “Root Motion Node,” but I don’t know if this is a blocker).
Exporting by hand got tedious really fast. Especially if I wanted to export only some objects in the scene (like, not all the WGT_XXX meshes from Rigify) and had to select them one-by-one each time to use the ‘Selected Objects Only’ option. So I wrote a Python script (actor-export.py) that exports only the objects I want with the correct settings every time. I run it via a shell script:
#!/bin/sh
if [ ./.Models/Spotlight.blend -nt ./Spotlight.fbx ]
then
blender \
./.Models/Spotlight.blend \
--python ../../../../Blender/actor-export.py \
--background \
-- \
./Spotlight.fbx \
Mounting \
Case \
Shades
fi
To manage animations, I used Blender’s library linking feature. Like, I have “Character.blend” and “ClimbingAnimations.bkend”, “FightingAnimations.blend” etc. linking to that file without duplicating the meshes/rigs. Also very useful to created paired animations (i.e. “Character.blend” + “Horse.blend” linked into “RidingAnimations.blend”).
Exporting animations with linked+proxied armatures kept breaking across different Blender versions, so I wrote a script that fixes it once and for all: its opens the original “Character.blend,” appends (in memory) all animations from the animation .blend file, creats a dummy mesh to export, then exports only the dummy mesh + animations, finally closes without saving (animation-export.py) 
#!/bin/sh
if [ ./.Models/RidingAnimations.blend -nt ./RidingAnimations.Character.fbx ]
then
blender \
../../Actors/Character/.Models/Character.Rigify.blend \
--background \
--enable-autoexec \
--python ../../../Blender/animation-export.py \
-- \
./.Models/RidingAnimations.blend \
*-Character \
./RidingAnimations.Character.fbx
fi
With the scripts in place, I’m very happy with the Blender workflow. The edit-export-test cycle is extremely fast (since I only export/import the 5 or so animations in an animation library).