His wife, Professor Josiane Heulot-Serre, was a chemist; she also was the director of the Ecole Normale Supérieure de Jeunes Filles.

Together with Cartan, Serre established the technique of using Eilenberg–MacLane spaces for computing homotopy groups of spheres, which at that time was one of the major problems in topology.

In the 1950s and 1960s, a fruitful collaboration between Serre and the two-years-younger Alexander Grothendieck led to important foundational work, much of it motivated by the Weil conjectures.

[4] Even at an early stage in his work Serre had perceived a need to construct more general and refined cohomology theories to tackle the Weil conjectures.

Around 1958 Serre suggested that isotrivial principal bundles on algebraic varieties – those that become trivial after pullback by a finite étale map – are important.

Amongst his most original contributions were: his "Conjecture II" (still open) on Galois cohomology; his use of group actions on trees (with Hyman Bass); the Borel–Serre compactification; results on the number of points of curves over finite fields; Galois representations in ℓ-adic cohomology and the proof that these representations have often a "large" image; the concept of p-adic modular form; and the Serre conjecture (now a theorem) on mod-p representations that made Fermat's Last Theorem a connected part of mainstream arithmetic geometry.

This question led to a great deal of activity in commutative algebra, and was finally answered in the affirmative by Daniel Quillen and Andrei Suslin independently in 1976.