Known differences

As of 3.x release

Topics such as Cross-Origin, Content Security Policy, Mixed Content, Service Workers are ignored, given our server-side context.
On the upside, there are no forbidden headers.
res.url contains the final url when following redirects.
For convenience, res.body is a Node.js Readable stream, so decoding can be handled independently.
Similarly, req.body can either be null, a buffer or a Readable stream.
Also, you can handle rejected fetch requests through checking err.type and err.code. See ERROR-HANDLING.md for more info.
Only support res.text(), res.json(), res.blob(), res.arraybuffer(), res.buffer()
There is currently no built-in caching, as server-side caching varies by use-cases.
Current implementation lacks server-side cookie store, you will need to extract Set-Cookie headers manually.
If you are using res.clone() and writing an isomorphic app, note that stream on Node.js has a smaller internal buffer size (16Kb, aka highWaterMark) from client-side browsers (>1Mb, not consistent across browsers). Learn how to get around this.
Because Node.js stream doesn't expose a disturbed property like Stream spec, using a consumed stream for new Response(body) will not set bodyUsed flag correctly.

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