In the Lesser Antilles they managed to establish a foothold following the colonization of St Kitts in 1624 and Barbados in 1626, and when the Sugar Revolution took off in the mid-seventeenth century, they brought in thousands of Africans to work the fields and mills as slave laborers. These Africans wrought a demographic revolution, replacing or joining with either the indigenous Caribs or the European settlers who were there as indentured servants.

The struggle between the northern Europeans and the Spanish spread southward in the mid to late seventeenth century, as English, Dutch, French and Spanish colonists, and in many cases their slaves from Africa first entered and then occupied the coast of The Guianas (which fell to the French, English and Dutch) and the Orinoco valley, which fell to the Spanish. The Dutch, allied with the Caribs of the Orinoco, would eventually carry the struggles deep into South America, first along the Orinoco and then along the northern reaches of the Amazon.

Since no European country had occupied much of Central America, gradually the English of Jamaica established alliances with the Miskito Kingdom of modern-day Nicaragua and Honduras, and then began logging on the coast of modern-day Belize. These interconnected commercial and diplomatic relations made up the Western Caribbean Zone which was in place in the early eighteenth century. In the Miskito Kingdom, the rise to power of the Miskito-Zambos, who originated in the survivors of a rebellion aboard a slave ship in the 1640s and the introduction of African slaves by British settlers within the Miskito area and in Belize, also transformed this area into one with a high percentage of persons of African descent as was found in most of the rest of the Caribbean.

From the 17th through the 19th century, the European colonial territories of the West Indies were the French West Indies, British West Indies, the Danish West Indies, the Netherlands Antilles (Dutch West Indies), and the Spanish West Indies. In 1916, Denmark sold the Danish West Indies to the United States for US $25 million in gold, per the Treaty of the Danish West Indies. The Danish West Indies became an insular area of the U.S., called the United States Virgin Islands.

Between 1958 and 1962, the United Kingdom reorganized all their West Indies island territories (except the British Virgin Islands and the Bahamas) into the West Indies Federation. They hoped that the Federation would coalesce into a single, independent nation. However, the Federation had limited powers, numerous practical problems, and a lack of popular support; consequently, it was dissolved by the British in 1963, with nine provinces eventually becoming independent sovereign states and four becoming current British Overseas Territories.

West Indies or West India was the namesake of several companies of the 17th and 18th centuries, including the Danish West India Company, the Dutch West India Company, the French West India Company, and the Swedish West India Company. West Indian is the official term used by the U.S. government to refer to people of the West Indies.