In vertebrate and invertebrate models, adrenocorticotropic hormone (ACTH) belongs to the melanocortin group of related peptides, which share a common precursor, pro-opiomelanocortin (POMC). Functional experiments indicate that in invertebrates, ACTH plays a major role in several biological functions. ACTH, whose effects have been conserved during evolution more than its amino acidic sequence, is, directly or indirectly, able to contrast agents that perturb a body’s homeostasis. Here we review evidence highlighting the involvement of ACTH and ACTH-like molecules in the response of invertebrate models versus immune, environmental and parasitic challenges.