I own a large home (4800 sq ft) with a 1/2 length basement 1/2 length crawl space.  The ceiling/attic space is obvious quite large given this layout!

The home was built in 1979, it has newer windows with good caulk and good doors that seal well (we get some good winds so I've recaulked some areas with leaks and such already). I would like to do some work to reduce air infiltration particularly in the ceiling/attic interface.  There ARE some very bad old tech ceiling can lights that I need to probably just give up on and replace with sealed/IC rated cans soon.  Another set of cans are IC but I still believe are fairly leaky and need boxes built around them or some other commercial solution to reduce air infiltration.

Many of the electrical boxes (ceiling lights, ceiling fans) are also poorly sealed and require some work. Those are fairly easy to locate and caulk/foam down a bit.  The big question is, with about 20-24 inches of blown in insulation up there, so I go up, rack that stuff out of the way and go in with foam and seal the ALL the penetrations to get a good result or should I just focus on the 'big stuff'?  The attic is easy to work in, but the ceiling of the house is typical sheetrock with no other barrier/material/etc.

Love to here thoughts.

With air sealing it's always better to start with the big holes first, but death by 1000 leaks is still a problem. In some situations you may be able to reduce the flow of the 1000 micro-leaks using a vapor permeable housewrap (Typar, Tyvek, etc) either over the insulation layer, or stapled to the rafters, preserving soffit/ridge ventilation schemes. Edges & seams of any sheet materials still need to be air-sealed (tape/foam/caulk). Even with a sheet solution it's still worth fixing all of the easy leaks at the electrical boxes, etc.

Also note, stack effect forces driving infiltration are as-easily interrupted by sealing the bottom as by sealing the top. Band joists & foundation sills are one of the biggest un-treated air leaks in most homes. (Very few 1970s homes have insulated foundations as well. A combination of semi-permeable rigid foam and studwall with un-faced batts can be a low-cost way to retrofit basements & crawls. See: http://www.buildingscience.com/documents/reports/rr-1003-building-america-high-r-foundations-case-study-analysis and http://www.buildingscience.com/documents/reports/rr-1003-building-america-high-r-foundations-case-study-analysis

Many homes will have less obvious flue or plumbing chases that run from basement to attic or conditioned space to attic too. If the basement ceiling is unfinished keep an eye out for those. When in doubt, air-seal any penetration between the basement & first floor, and weatherstrip & door-sweep any basement doors.

If you have atmospheric-drafted combustion equipment (furnaces/boilers, water heaters, etc) check for backdrafting issues after any serious round of air-sealing just to be on the safe side. And whenever you replace said equipment, take sealed-combustion (or at least forced-draft) options over atmospheric-draft- it's both a safety issue and an infiltration driver. Flues put the building under negative pressure relative to the outdoors (it's what' they're designed to do), sucking outdoor air in. Flue dampers don't seal tight, they only slow it down. Fireplace flues can be some of the worst infiltration leaks, but retrofit top-sealing dampers can often take care of it.

If you seal both the top and bottom of the stack, the background infiltration rates plummet, even when there's still leakage in the middle. But fixing those is also worthwhile- the wind does blow, and even though the stack effect is lower from those leaks, it's never zero.

Leakage from the outside through exterior studwall cavities is also pretty common, but the solutions will vary. Even partition-walls can be real contributors- sealing plumbing & electrical penetrations into ANY vertical structure reduces the flow of that parasitic-stack.