Brown adipocytes regulate energy expenditure via mitochondrial uncoupling. This makes these fat cells attractive therapeutic targets to tackle the burgeoning issue of obesity, which itself is coupled to insulin resistance, type 2 diabetes, cardiovascular and fatty liver disease. Recent research has revealed a complex network underlying brown fat cell differentiation and thermogenic activation, involving secreted factors, signal transduction, metabolic pathways and gene regulatory components. Given that brown fat is now reported to be present in adult humans, it is desirable to harness the knowledge from each network module to design effective therapeutic strategies. In this review, we will present a systems perspective on brown adipogenesis and the subsequent metabolic activation of brown adipocytes by integrating signaling, metabolic and gene regulatory modules with a specific focus on known 'druggable' targets within each module.