Tumor necrosis factor (TNF)-α is a highly conserved proinflammatory cytokine with important functions in immunity, tissue repair, and cellular homeostasis. Due to the simplicity of the Drosophila TNF-TNF receptor (TNFR) system and a broad genetic toolbox, the fly has played a pivotal role in deciphering the mechanisms underlying TNF-mediated physiological and pathological functions. In this review, we summarize the recent advances in our understanding of how local and systemic sources of Egr/TNF contribute to its antitumor and tumor-promoting properties, and its emerging functions in adaptive growth responses, sleep regulation, and adult tissue homeostasis. The recent annotation of TNF as an adipokine and its indisputable contribution to obesity- and cancer-associated metabolic diseases have provoked a new area of research focusing on its dual function in regulating immunity and energy homeostasis. Here, we discuss the role of TNFR signaling in coupling immune and metabolic processes and how this might be relevant in the adaption of host to environmental stresses, or, in the case of obesity, promote metabolic derangements and disease.