I think the differences between 4.x and 5.x are very significant and I would class it as a "Major" upgrade, which can be painful if not planned out correctly. There are also significant differences in the way you manage and administer a vSphere 5.x environment, e.g. vSphere Web Client, HA changes, etc...
The way you would approach it also depends on what version you are upgrading from and to. However, make sure you have vCenter 5.1 FIRST and ideally Update Manager 5.1(if licensed). The biggest change and potentially the pitfalls will be in vCenter 5.1. Please see link for further info - VMware KB: Upgrading to vCenter Server 5.1 best practices .
Once you have the above working correctly, you have choices in how to deploy your ESXi 5.1 Hosts - VMware KB: Methods for upgrading to ESXi 5.1 .
Finally you can upgrade the VM Hardware and VM Tools to latest versions on all your VMs. Please note, you can only upgrade the VM Hardware using the vSphere Web Client.
Good Luck !
VCP6-DCV, VCP5, CCNA, MCTS 2008R2, MCSA 2008R2, CCA, ITIL.
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