Abstract Psychrophilic organisms thriving at near-zero temperatures synthesize cold-adapted enzymes to sustain cell metabolism. These enzymes have overcome the reduced molecular kinetic energy and increased viscosity inherent to their environment and maintained high catalytic rates by development of a diverse range of structural solutions. Most commonly, they are characterized by a high flexibility coupled with an intrinsic structural instability and reduced substrate affinity. However, this paradigm for cold-adaptation is not universal as some cold-active enzymes with high stability and/or high substrate affinity and/or even an unaltered flexibility have been reported, pointing to alternative adaptation strategies. Indeed, cold-adaptation can involve any of a number of a diverse range of structural modifications, or combinations of modifications, depending on the enzyme involved, its function, structure, stability, and evolutionary history. This paper presents the challenges, properties, and adaptation strategies of these enzymes.