While it is highly accepted that ADAM family members with ubiquitous expression patterns, such as ADAM10 and ADAM17 have major roles in homoeostasis and pathology, ADAM8 was initially considered as an immune-specific ADAM with a cell-specific expression pattern. Therefore, ADAM8 had a “sleeping beauty” existence for many years, and has recently come back into focus as it was detected under several pathological conditions. These were found to typically involve inflammation and remodelling of the extracellular matrix, including cancers and serious respiratory diseases such as asthma. In these diseases, induced expression of ADAM8 by different stimuli results in cleavage of various substrates, including cell adhesion molecules, cytokine receptors, and ECM components. Involvement of ADAM8 in individual diseases indicates its usefulness as both a diagnostic and prognostic marker. Even more strikingly, as ADAM8 progressively emerges as a key effector in pathological processes, so does its attractiveness as a therapeutic target rather than being a mere indicator of disease and its progression. This is encouraged by analysis of ADAM8 null mice, identifying no adverse phenotype in the absence of functional ADAM8. Thus, ADAM8 potentially is an attractive drug target in a variety of diseases. In this review, the current knowledge on ADAM8 in diseases and avenues for specific inhibition based on unique biochemical features of ADAM8 will be presented.