One of the primary concerns of the novel is the blurring of boundaries between human and non-human, culture and nature, and self and other. The Shimmer's presence has disrupted the natural order, causing strange mutations and hybrids to emerge. The Expedition's encounters with these creatures serve as a catalyst for exploring the limits of human identity and the concept of self.

The novel's use of the unknown and the unknowable serves as a commentary on the limits of human knowledge and understanding. Vandermeer suggests that there are forces beyond human control, which can disrupt and transform our understanding of the world.

"Annihilation" is also a deeply environmental novel, which explores the consequences of human actions on the natural world. The Shimmer's presence serves as a metaphor for the destructive power of human activity, which has ravaged the environment and disrupted the natural order.

The novel's exploration of the unknown, the blurring of boundaries, and the power of the environment serve as a commentary on the limits of human knowledge and understanding. As a work of eco-fiction, "Annihilation" serves as a warning about the dangers of environmental degradation and the consequences of human neglect.