Specifying identify files for specific hosts, using bastion hosts (ProxyJump), etc. For example, my laptop SSH config detects when I'm not on my university network or VPN and adds a ProxyJump through the department bastion host, but connects directly when I'm on the network. Configurations like that break when software makes too many assumptions about how ssh is configured.
I use a Yubikey for some of my keys, and I've never used an "agent", don't know how, and don't want to start, unless someone can give me a good reason to
ssh-keygen -t ed25519-sk
that's all you need to use a Yubikey with SSH
also, don't know a good security researcher who uses agents (some even use ssh config to limit which keys are even tried per domain)
ssh config hacks are also a must if you have, say, two or more identities to github.com for example.