Soft tissue fillers are heterogeneous products widely utilized in aesthetic medicine to enhance lip and facial volume, define contour features, and mitigate signs of aging. The increasing use of these materials makes it necessary to comprehensively understand the histomorphological modifications that result from their interaction with host tissues and the implications of their possible adverse reactions. This chapter explores the histopathological profiles of various fillers, including human tissue collagen matrix, acellular human dermal matrix, bovine collagen, liquid silicone, polymethylmethacrylate (PMMA), hyaluronic acid (HA), calcium hydroxyapatite (CaHA), hydroxyapatite, poly-L-lactic acid (PLLA), mineral oil, hydrogel, polyalkylimide, and autologous fat transfer. This chapter presents a comparative analysis of their microscopic appearances, histological differences, and adverse reaction profiles, drawing on recent literature to provide a well-rounded overview of these materials in clinical practice.