First Cause begins in a news van, as a reporter and her cameraman are on their way to cover a street fair in downtown Manhattan. Their calm is interrupted by an exploding truck, not far from their van as it passes through Times Square. Mobilizing to report from the scene, they are informed by their superiors that an explosion has also occurred downtown. They scarcely have time to respond to this new bit of information when a second bomb explodes, ending their broadcast.

We then meet Adam Grey, a New York City freelance journalist, as he wakes up in a hospital bed. Through Adam's conversation with his intern, we learn that similar explosions have occurred in most of the world's major cities and power centers. The attacks were well planned; most governments have lost huge portions of their leadership, scores of civilians have been killed, and a rising panic has begun to sweep the world. The United States Cabinet has been almost entirely lost, and a Senator named Cyrus Reardon has been selected to lead a provisional Cabinet from a secret location.

Upon reflection, Adam realizes that his hospital stay is the result of an incident in a stairwell, involving a recent acquaintance named Angela. After a brief courtship, Angela seems to have indirectly caused his hospitalization...and then disappeared.

As the world stumbles its way through the crisis, news agencies and the world's surviving leaders receive a cryptic letter, claiming to be from the attackers and making outlandish proclamations. Angela resurfaces, informing Adam that 'the letters are true' and she is connected to their source. She asks Adam to use his connections to alert President Reardon of the nature of the threat they face; he reluctantly agrees...