The main story arc is set roughly 6 million years from now. By this point, humanity has spread throughout the Milky Way galaxy, which appears devoid of any other sentient life. The galaxy is dominated by civilisations of humans and various posthumans of widely varying levels of development. A civilisation of robots, known as the Machine People, has also evolved and coexists peacefully with humanity. Technologies that are available include anti-gravity, inertial dampening, force fields, and stasis fields. Also of note is the "Absence"- the mysterious disappearance of the Andromeda Galaxy.
Large-scale human civilisations almost invariably seem to fall within a few millennia (referred to as "turnover"), the limits of sub-lightspeed travel making it too difficult to hold interstellar empires together. Consequently, the most powerful entities in the galaxy are the "Lines"- organisations made of "shatterlings". The Lines do not inhabit planets, but instead travel through space, holding reunions after they've performed a "circuit" of the galaxy; something that takes about 200,000 years.
House of Suns concerns the Gentian Line, also known as the House of Flowers; 999 clones (or "shatterlings"), male and female, of Abigail Gentian, with Abigail being the 1,000th shatterling (exactly which of the 1,000 shatterlings is the original Abigail Gentian is unknown). The clones and Abigail travel the Milky Way Galaxy helping young civilizations, collecting knowledge and experiencing what the universe has to offer.