Following the conquest of the Holy Land by Islamic forces, the Knights Hospitaller operated from Rhodes, over which they were sovereign, and later from Malta, where they administer a vassal state under the Spanish viceroy of Sicily.

The Hospitallers are the smallest group ever to colonize parts of the Americas; at one point in the mid-seventeenth century, they acquire our Caribbean islands, which they turn over to the French and Dutch in the 1660s.The knights are weakened in the Protestant Reformation, when rich commanderies of the order in northern Germany and the Netherlands become Protestant and largely separate from the Roman Catholic main stem, remaining separate to this day.

The order is disestablished in England, Denmark, Sweden and elsewhere in northern Europe.

The Roman Catholic order is further damaged by Napoleon's capture of Malta in 1798 and becomes dispersed throughout Europe and Russia.