Two decades of inflammasome research has led to a vast body of knowledge on the complex regulatory mechanisms and pathological roles of canonical and non-canonical inflammasome activation in a plethora of research models of primarily rodent origin. More recently, the field has made notable progress in characterizing human-specific inflammasomes and their regulation mechanisms, including an expansion of inflammasome biology to adaptive immune cells. These exciting developments in basic research have been accompanied by potentially transformative results from large clinical trials and translational efforts to develop inflammasome-targeted small molecule inhibitors for therapeutic use. Here, we will discuss recent findings in the field with a specific emphasis on activation mechanisms of human inflammasomes and their potential role in auto-inflammatory, metabolic and neoplastic diseases.