The immune system has lately been linked to managing systemic metabolic homeostasis, in addition to its conventional role in anti-infectious and anti-neoplastic defence. Similarly, various metabolic mechanisms were involved in immunological homeostasis maintenance. Given the importance of immune-metabolic alignment in promoting "metabolic health" and its fundamental role in endorsing appropriate adaptations to a host's ever-changing environmental setup, we highlight current understanding of this immune-metabolic cross-talk and illustrate the role of the gut microbiota, diet, and host genetic and epigenetic factors in this immune-endocrine communication, paving the way for future research and promising therapeutics.