Keratoconus (KC) is a corneal ectatic condition characterized by focal structural changes, resulting in progressive thinning, biomechanical weakening, and steeping of the cornea that can lead to worsening visual acuity due to irregular astigmatism and corneal scarring in more advanced cases. It is a relatively common ectatic disease of the cornea predominantly affecting the younger population. Despite its worldwide prevalence, its incidence is rather varied with a higher incidence among the Middle Eastern and South Asian population. Dysregulated corneal extracellular matrix remodeling underlies KC pathogenesis. However, a lack of absolute clarity regarding the factors that initiate and drive progression poses a significant challenge in its prevention and management. KC is a complex multifactorial disease as it is associated with a wide variety of etiological factors such as environmental stimuli/insults, oxidative stress, genetic predisposition, comorbidities, and eye rubbing. A series of studies using corneal tissues (epithelium, stroma), cultured corneal fibroblasts/keratocytes, tear fluid, aqueous humor, and blood from KC subjects has reported significant alterations in various biochemical factors such as extracellular matrix components, cellular homeostasis regulators, inflammatory factors, hormones, metabolic products, and chemical elements. It has become apparent that alterations in the biochemical mediators (related to various etiologies) could contribute to KC pathogenesis by altering the dynamics of extracellular matrix remodeling events such as collagen deposition, degradation, and cross-linking in the cornea. Determining key disease contributing biochemical mediators would aid in disease monitoring, prediction or abatement of disease progression, and development of targeted therapeutics to improve disease prognosis.