A Song of Ice and Fire follows three principal storylines, divided by geography and participants.

The first storyline, set in the Seven Kingdoms themselves, chronicles a many-sided struggle for the Iron Throne that develops after King Robert's death. The throne is claimed by his son Joffrey, supported by his mother's powerful family, House Lannister. However, Lord Eddard Stark, King Robert's Hand, finds out Robert's children are illegitimate, and that the throne should therefore fall to Robert's unpopular eldest brother, Stannis. Robert's charismatic and popular youngest brother, Renly, also places a claim, openly disregarding the order of precedence, with the support of the powerful House Tyrell. While the claimants battle for the Iron Throne, Robb Stark, Lord Eddard Stark's heir, is proclaimed King in the North as the northmen and their allies in the Riverlands seek to return to self-rule. Likewise, Balon Greyjoy also (re-)claims the ancient throne of his own region, the Iron Islands, with an eye toward independence. This so-called War of the Five Kings is the principal storyline of the first four novels; indeed, the fourth novel primarily concerns Westeros's recovery from it in the face of the coming winter and the political machinations of those seeking to gain in its aftermath.

The second storyline is set on the extreme northern border of Westeros. Here, many thousands of years ago, a huge wall of ice and gravel was constructed by both magic and labor to defend Westeros from the threat of The Others, a race of now-mythical creatures living in the uttermost north. This Wall, 300 miles (480 km) long and 700 feet (210 m) tall, is defended and maintained by the Sworn Brotherhood of the Night's Watch, whose duty is to guard the kingdom against the Others. By the time of the novels, the Others have not been seen in over 8,000 years, and the Night's Watch has devolved into essentially a penal colony: it is badly under-strength, manned primarily by criminals and refugees with only a few knights or men of honor to stiffen them, and spends most of its time dealing with the human "wildlings" or "free folk" who live beyond the Wall. This storyline is told primarily through the eyes of Jon Snow, bastard son of Eddard Stark, as he rises through the ranks of the Watch, learns the true nature of the threat from the north, and prepares to defend the realm even though the people of Westeros are too busy warring to send support. By the end of the third volume, this storyline is somewhat entangled with the civil war to the south.

The third storyline is set on the huge eastern continent of Essos, across the narrow sea, and follows the adventures of Daenerys Targaryen, the last scion of House Targaryen and another claimant to the Iron Throne. Daenerys's adventures showcase her growing ability as she rises from a pauper sold into a dynastic marriage to a barbarian warlord to a powerful and canny ruler in her own right. Her rise is aided by the birth of three dragons, creatures thought long extinct, from fossilized eggs given to her as wedding gifts. Because her family standard is the dragon, these creatures are of symbolic value before they have grown big enough to be of tactical use. Though her story is separated from the others by many thousands of miles, her stated goal is to reclaim the Iron Throne.