Severe asthma (SA) is a refractory condition that does not respond well to conventional treatments. Patients with SA have heterogenetic endotypes. Endotypes for SA can be classified as type 2 cytokine-high and type 2 cytokine-low. The condition can also be classified as eosinophilic, neutrophilic, mixed, and paucigranulocytic SA. Abnormalities in TH1 and TH17 cytokines can be present in some SA patients. Innate lymphoid cells, airway smooth muscle cells, and lung epithelial cells have important roles in the disease. Viral infections, bacterial infections, fungal infections, smoking, allergens, and pollutants are major triggers that determine the severity of the disease. Biologics have been proven to be effective for some type 2 high patients. Multi-omics approaches, including genomics, transcriptomics, proteomics, metabolomics, and metagenomics, have identified many novel genes or molecules that could serve as biomarkers or potential therapeutic targets for SA. Investigations of the mechanisms of novel genes and molecules will help us understand the condition and find new treatment means for SA in the future.