Many genodermatoses present early in life with a chronic and often debilitating, progressive course with multi-organ involvement and significant morbidity or even mortality. Therefore, timely determination of the correct diagnosis is highly needed to improve approaches of patient care. Considering the common geno- and phenotypic variability of genodermatoses, this is most accurately provided by means of molecular diagnostics. Characterization of disease-causing genetic aberrations along an algorithmic diagnostic approach further paves the way for strategies of targeted therapeutic intervention.