Although the physiological roles of p38γ and p38δ signalling pathways are largely unknown, new genetic and pharmacological tools are providing groundbreaking information on the function of these two stress-activated protein kinases. Recent studies show the importance of p38γ and p38δ in the regulation of processes as diverse as cytokine production, protein synthesis, exocytosis, cell migration, gene expression, and neuron activity, which have an acute impact on the development of pathologies related to inflammation, diabetes, neurodegeneration, and cancer. These recent breakthroughs are resolving some of the questions that have long been asked regarding the function of p38γ and p38δ in biology and pathology. The roles of the alternative p38 mitogen-activated protein kinases (MAPKs) p38γ and p38δ have been disregarded in many studies and remain largely unknown. The identification of novel p38γ and p38δ substrates ascribes new biological functions to these kinases. The finding that p38γ and p38δ modulate the inflammatory/immune response is a major breakthrough in signalling research and positions these kinases as potential therapeutic targets. Overall and tissue-specific p38γ and p38δ that these kinases also have a relevant role in the regulation of tumour development, cardiac hypertrophy, and glucose homeostasis.