Uric acid crystals [monosodium urate (MSU)] have emerged as an important factor for both gouty arthritis and immune regulation. This simple crystalline structure appears to activate innate host defense mechanisms in multiple ways and triggers robust inflammation and immune activation. The recognition mechanisms of MSU following its phase change from soluble uric acid are diverse, involving both protein receptors and non-specific plasma membrane attachment. Upon contact with host cells, MSU induces a set of membrane events that trigger Syk and PI3K activation, phagocytosis, and cytokine production. Having entered the cell, MSU further triggers NALP3 inflammasome activation and induces the production of IL-1 beta, likely inducing a full spectrum of inflammation. This review describes the recognition mechanisms and activation pathways involved in MSU-mediated inflammation and adjuvanticity and hypothesizes that direct membrane binding by solid surfaces, such as MSU, may function as a generic mechanism in tissue responses to particulate and crystalline structures.