I copied the discussion below from the Net's "Ask Your Neighbor" page (/ask_your_neighbor/ask_your_neighbor/). In turn, the original question and answer were copied, with permission, from the T&T (Trawlers and Trawlering) list.
Anyway, I thought this discussion contained plenty of good info which should also have a place here on the Net's "Florida Keys" section.

We're heading from Miami south to the keys, Marathon, probably Key West  eventually. 1st time. Maerin draws an even 5 ft. We avoid marinas except as a last  resort. We have no schedule.
Our plan it to head down Hawk Channel, from what we can gather from all the information we have available, inside is doable but I'm crazy about  having a lot of contact with the bottom. I'd rather stay in deeper water  and be able to relax a bit, at least for my initiation to cruising the  Keys. Seems most of the cruising guides are directed toward 3 ft. of draft!
I'd welcome any input, especially recommendations of spots where we might be able to anchor for a day or so as we make our way south.
Steve Sipe
Solo 4303 "Maerin"
Lying N of Belle Is. Miami Beach

Steve,
Plenty of deep water in Hawks Channel. Our usual run is Key Biscayne/Miami to Rodriguez Key, To Marathon and Key West can be done from there on a long day. Look for strong easterly winds form Miami to Marathon and don't leave Miami until they either go light or go northwest. Its a great trip and just watch the depth sounder going into Rodriguez. We were based out of the Keys for 10 years with a 6 foot draft. Chuck
Steve

I've done the inside on my boat many time with a good 4' draft and really no problems. it's all well marked and a pleasant trip.
I took a 54 hatt down last year, the winds were strong resulting in water being pushed out of florida bay, it was fine.  kept slow (hull speed), churned some sand behind the boat in a couple of spots but never touched.
The only shallow spots are at the eastern entrance to Dusenbverry Creek, in KL, about 5.5' MLW, and a sport  on a north side of KL,  exiting the last cut before the run to Pigeon creek, again 5.5 MLW.
There are many nice spots to anchor out.. in biscayne bay, Eliott Key and Boca Chita are must stop at… you can take 5' into boca chita, it's about 5.5 between the final set of buoys near the island., again that's MLW, you can play the tide for safety.
Further down, you can anchor north of Pigeon key, plenty of water there, near Butternut keys.
From there, go outside at Snake Creek, you can grab a mooring at Indian Key.
Marathon is ok, they have moorings now, but I prefer anchoring on the other side of hte 7 miles bridge, by Bahia Honda, either between the bridges by the park, or a couple miles north behind the keys on the east side of big spanish channel.  New Found Harbor a few miles south is also a protected anchorage.
Pascal