Harlequin ichthyosis (HI) is a rare, severe, and congenital disorder that is often life-threatening, characterized by thick, rigid skin and large, diamond-shaped plates. These skin changes are not only aesthetically distressing but also pose significant functional challenges for affected individuals, such as impaired thermoregulation, restricted mobility, and heightened susceptibility to infections. The condition arises due to mutations in the ABCA12 gene, which encodes a critical lipid transporter protein essential for skin barrier function. Historically, HI was nearly fatal in the neonatal period due to complications such as sepsis, respiratory distress, and electrolyte imbalances from excessive transepidermal water loss. However, advances in intensive neonatal care–including humidified incubators, prophylactic antibiotics, and early nutritional support–have improved survival rates to over 50% in recent decades. Despite these gains, lifelong morbidity persists, with survivors often facing chronic skin inflammation, recurrent infections, and psychosocial challenges stemming from disease visibility. This review paper explores the genetic underpinnings of HI, focusing on ABCA12 mutations and their effects on epidermal differentiation and the formation of the skin’s stratum corneum. By utilizing advanced bioinformatics tools, including whole-exome sequencing, researchers are now able to identify mutations with high precision and investigate the genotype–phenotype correlations in HI. The review also examines the clinical challenges posed by HI, therapeutic strategies currently available, and the potential for innovative treatments such as gene therapy and skin-engineering. The paper aims to highlight the vital role bioinformatics plays in understanding the molecular mechanisms of HI, facilitating earlier diagnosis and personalized management for affected individuals. Advances in genetic research have provided new hope for improved outcomes and better quality of life for those affected by this debilitating condition.