Zigbee channel and interference. Check the hub channel and your Wifi.
Plan out your mesh probably for each hub. Maybe hub per floor or per footage of your house.
Try to have rules running on the hub with the actual device.
For mesh, my house is small enough that I'm not worried about coverage at the moment. A single hub can cover the whole thing. Right now, both are placed in the center of the house, a few feet away from my wifi router, but the hubs are right next to each other. I guess I could move one to another room if needed, but then I lose the advantage of it being centrally located.
I was planning to have only zigbee bulbs connect to the second hub, so in most cases rules would involve devices on both hubs - i.e. motion sensors connected to hub 1 trigger lights on hub 2. Does that make sense?
This separation is a "general" guidance to avoid bad bulbs. You have not stated what bulbs you are using or plan to use. If you say Osram/Lightify I'm going to say throw them away. If you say Sengled then this guidance of separate hub does not apply because those bulbs do not route and therefore are not a problem. So it's not a black and white type rule.
I would highly recommend HubConnect. It is quick and recently had a new release that makes it even better.
Everyone's usage will be different. And I'm guessing if you are a tinkerer, you're usage will change over time.
I bought a second hub, and moved all my "questionable" apps to it at first. I had a lot of devices going back and forth using HubConnect. I've slowly moved all but Chromecast Integration / TTS notifications back to the main hub. The Chromecast integration has some issues. Everything else is working well on the main hub. With this setup, only the main hub has the Z radios turned on.
As far as bulbs, I'd agree with @jeubanks about it depending on your type of bulbs. And also on whole bunches of things you can't quantify - mainly the environment they are in. My bulbs are in between Osram/Lightify and Sengled as far as playing well with others - I have all Hue bulbs. Some people have said they don't work well in your normal zigbee mesh, and I believe the reports. But personally I have had no issues (at least none that i have seen) with them all being directly connected to the same Hub as my other zigbee devices.
Personally I just have Hue, and use the Hue bridge for the lights. I also have a second hubitat that I use to run WebCoRE and Echo Speaks, with basically everything shared from the main hub via HubConnect. It seems to have helped with my hub slowness issue a lot. And the recent releases of WebCoRE has improved 10000% over how it operated last year.