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Simple Summary: The perspective of this paper will focus on high-resolution imaging of collagen alterations in high-grade serous ovarian cancer (HGSOC). We will highlight the use of the collagen-specific/sensitive Second Harmonic Generation (SHG) microscopy in delineating changes across multiple size scales between HGSOC, other ovarian tumors, HGSOC precursors and normal tissues. Specifically, we utilize machine learning techniques to differentiate these tissues with high accuracy and further exploit the underlying SHG physics to determine sub-resolution information on fibril assembly and macro/supramolecular collagen structure. We also describe how SHG can be combined with other modalities including fluorescence and optical coherence tomography (OCT). Lastly, we discuss challenges and opportunities for translation to in vivo applications, focusing on advances in endoscopic technology. We postulate that successful diagnosis/treatment of HGSOC requires an integrated approach of ex vivo microscopic and molecular analyses to establish the foundation for in vivo imaging. High-grade serous ovarian cancer (HGSOC) is the predominant subtype of ovarian cancer (OC), occurring in more than 80% of patients diagnosed with this malignancy. Histological and genetic analysis have confirmed the secretory epithelial of the fallopian tube (FT) as a major site of origin of HGSOC. Although there have been significant strides in our understanding of this disease, early stage detection and diagnosis are still rare. Current clinical imaging modalities lack the ability to detect early stage pathogenesis in the fallopian tubes and the ovaries. However, there are several microscopic imaging techniques used to analyze the structural modifications in the extracellular matrix (ECM) protein collagen in ex vivo FT and ovarian tissues that potentially can be modified to fit the clinical setting. In this perspective, we evaluate and compare the myriad of optical tools available to visualize these alterations and the invaluable insights these data provide on HGSOC initiation. We also discuss the clinical implications of these findings and how these data may help novel tools for early diagnosis of HGSOC. [ABSTRACT FROM AUTHOR]