Background: Striae distensae, commonly known as stretch marks, are cutaneous lesions that accompany the hormonal upheavals of the major stages of life: puberty and pregnancy. Stretch marks occur in 90% of women, and they appear as red or purple lines that slowly fade to pale lines on the skin. There have been few studies regarding stretch mark origins, and new preventive and corrective treatments are needed. Aims: The aim of this work was to understand the primary genes and proteins involved in the regulation of striae compared to normal skin and to identify the differentially expressed genes and biochemical aspects of SA and SR Importantly, this is the first published study to use a molecular high-throughput approach combined with in vivo evaluation. Methods: In this study, we analyzed the molecular differences between skin with and without stretch marks (rubra [SR] and alba [SA]) of female volunteers using DNA microarray (Whole Human Genome Microarray Kit, 4×44 K, Agilent Technologies) analyses of cutaneous biopsies (2 mm) and in vivo confocal Raman spectroscopy of selected buttock regions, a technique recently introduced as a noninvasive skin evaluation method. Results: We identified gene expression alterations related to ECM, cellular homeostasis, and hormones such as secretoglobulins. Spectral analyses of collagen, fibrillin, and glycosaminoglycans were conducted by Raman spectroscopy at different skin depths. The main differences observed when comparing skin with and without stretch marks were at depths between 75 and 95 μm, corresponding to the dermalepidermal junction and dermis regions and showing differences between normal skin and stretched skin regarding collagen, collagen hydration, and elastin fibers. Conclusion: The results obtained by RNA and protein analyses are complementary and show that significant changes occur in the skin affected by stretch marks. These results suggest new strategies and opportunities to treat this skin disorder and for the development of new and eficiente cosmetic products. K E Y W O R D S molecular biology, Raman, striae distensae | 191 SCHUCK et al. 1 | INTRODUC TI ON Striae distensae (SD), or stretch marks, are linear, atrophic, well-defined cutaneous lesions that occur secondary to changes in connective tissue, which can be associated with obesity, growth spurts, or excess steroids. Many researchers believe that the pathogenesis of SD involves abnormalities of elastic fibers, collagen fibrils, or other ECM components 1 ; however, the specific mechanisms involved are still unclear. Different categories can be used to classify striae, such as striated atrophy, striae distensae, traumatic striae, and striae gravidarum (related to pregnancy), among others. They are normally parallel to each other and perpendicular to the cleft of the skin, suggesting a localized elastic imbalance. 2,3 Striae can be considered a type of dermal scarring, where there is a collagen rupture and separation, and this gap is filled by newly synthesized and realigned collagen. 5,6 In the early stag...