With the exception of fibroepithelial stromal polyp, the entities covered herein are uncommon and as such a broad differential diagnosis must be considered when evaluating a mesenchymal lesion in the vulvovaginal region. This may be narrowed by demographic (e.g., prepubertal vulvar fibroma and embryonal rhabdomyosarcoma in young women), clinical presentation (indolent versus rapidly growing mass, superficial versus deep), and morphology (myxoid versus fibromatous stroma; uniform versus fluctuating cellularity, cellular lineage—smooth muscle, adipocytic, fibroblastic/myofibroblastic, vascular, or peripheral nerve sheath). Immunohistochemistry may be utilized—noting that the anogenital mesenchyme shows peculiarly innate desmin expression, as do many of its derivative tumors without genuine myogenic, myofibroblastic, or myoepithelial differentiation. As such, categorically nonsensitive and nonspecific antibodies (i.e., vimentin, SMA, desmin, CD34, ER, and PR) should be employed conservatively, if at all, toward parsing any of these lesions. A select few harbor recurrent genetic abnormalities (loss of the 13q14 locus encoding RB1 in cellular angiofibroma and mammary-type myofibroblastoma, and rearrangement of the 12q13 locus encoding HMGA2 in aggressive angiomyxoma) which may be harnessed via immunohistochemistry or molecular modalities toward characterization. In most others, the diagnosis relies wholly upon histopathologic features. In any spindle cell proliferation of the vulva or vagina, acknowledging nonmesenchymal malignancies, such as spindled invasive squamous cell carcinoma, melanoma, and adenocarcinoma—is imperative, and these should be categorically excluded. Entities in this section are stratified into benign, locally aggressive, and malignant categories (excepting smooth muscle neoplasia, the spectrum of which is addressed sequentially). While most are indolent, parameters critical for certain lesions with a documented risk of local recurrence (i.e., margin status, extent of superficial and/or deep soft tissue involvement) are also detailed. The chapter concludes with a discussion of selected mesenchymal proliferations involving pelvic and inguinal lymph nodes that require awareness by the pathologist, as lymph node sampling is often part of the surgical management of patients with gynecologic cancer.