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The rationale for this issue, dedicated to the non-antimicrobial activities of tetracyclines (TCs) as matrix metalloproteinase (and cytokine) - inhibitors, and clinical applications of these properties, is addressed in this introduction. From a historical perspective, the author describes two "breakthrough" experiments that opened this field: (1) the discovery of animal collagenase, the first of a series of matrix metalloproteinases (MMPs) which are now known to be essential mediators of collagen-and connective tissue-destruction including bone loss during various diseases; and (2) the discovery by the author and his team of the unexpected ability of TCs to inhibit these MMPs, and by mechanisms unrelated to the antibiotic activity of these drugs. This led to the development of (i) non-antimicrobial formulations of TCs, ie., sub-antimicrobial-dose doxycycline which resulted in two approved drugs, one for the treatment of periodontal disease, the other for a chronic inflammatory skin disease, and (ii) non-antimicrobial compositions of TCs, ie., the chemically-modified TCs or CMTs or COLs--one of which has shown evidence of efficacy as an anti-angiogenesis agent in human clinical trials on a type of cancer. The development of the CMTs also resulted in the identification of the active site of the TC molecule as an MMP-inhibitor, the calcium and zinc binding site at carbon-11 and 12. And finally, the recently recognized importance of not excessively inhibiting the MMPs because basal levels are needed for various physiologic functions, and the therapeutic potential of TCs as inhibitors of intracellular not just extracellular MMP activity, are both introduced.