Severe cutaneous adverse drug reactions (SCARs) and targeted therapy-induced skin toxicities are major challenges in modern oncology and immunology. Classical SCARs, including Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), are associated with significant morbidity and mortality. In parallel, immune checkpoint inhibitors (ICIs), EGFR inhibitors (EGFRi), and MEK inhibitors (MEKi) have introduced novel inflammatory skin toxicities that often overlap clinically with classical SCARs but involve distinct pathogenic mechanisms. These disorders are now recognized as highly organized immune-mediated syndromes involving complex interactions between keratinocytes, cytotoxic T cells, eosinophils, neutrophils, dendritic cells, and inflammatory cytokine networks. SJS/TEN is driven by HLA-restricted cytotoxic CD8+ T-cell responses causing widespread keratinocyte death through granulysin, perforin/granzyme B, and Fas-FasL pathways. DRESS is characterized by systemic Th2/eosinophilic inflammation and viral reactivation, whereas AGEP is dominated by neutrophilic inflammation involving CXCL8, IL-17, and IL-36 signaling. EGFRi- and MEKi-induced toxicities primarily reflect epithelial stress and barrier dysfunction, while ICI-induced SCAR-like reactions result from loss of peripheral immune tolerance and exaggerated autoreactive T-cell activation. Despite recent advances, predictive biomarkers and mechanisms underlying tissue specificity remain poorly understood. Emerging technologies such as single-cell transcriptomics, spatial omics, and T-cell receptor sequencing are expected to improve mechanistic understanding and therapeutic targeting. Selective modulation of pathways including IL-17, IL-23, JAK/STAT, and IL-36 may offer novel strategies to control severe cutaneous inflammation while preserving antitumor efficacy. This review summarizes current knowledge on the immunopathogenesis, clinical features, and therapeutic perspectives of classical SCARs and anticancer therapy-induced severe skin toxicities.