Assuming you're using the BIOS INT 13h to read from the USB drive, then the BIOS will translate addresses as needed to work with the USB drive. Current boot loaders check for INT 13h extensions, and if present, use the extended version of read sectors, with a 64 bit logical sector address instead of CHS (cylinder / head / sector) to avoid the size limitations of the old interface. However a classic master boot record only has 32 bit values for starting sector and number of sectors for each primary partition, which limited drive size to 2 tera-bytes.
Wiki articles:
http://en.wikipedia.org/wiki/INT_13H
http://en.wikipedia.org/wiki/Master_boot_record
http://en.wikipedia.org/wiki/Master_boot_record#Sector_layout