These expansive uses have led to an increasing isolation of quinolone-resistant microorganisms, resulting in a worldwide epidemic of quinolone resistance from the mid-1990s onward [1]. Subsequently, quinolone resistance levels, selection, mechanisms, and dispersion pathways have been largely and increasingly studied since the 1960s [21; 33; 34; 35; 36; 37; 38; 39; 40; 41; 42; 43; 44; 45; 46; 47]. In the late 1970s, the implication of GyrA in the development of quinolone resistance was observed [48]. The relevant role of punctual mutations in quinolone targets encoding genes (_gyrA_ and _gyrB_, encoding DNA-Gyrase, and _parC_ and _parE_, encoding Topoisomerase IV), able to avoid or limit the ability of quinolones to interact with their targets, was clearly established in the 1980s and 1990s and was subsequently considered a universal pathway of the development of quinolone resistance in both Gram-negative or Gram-positive bacteria, including particular microorganisms, such as _Mycobacterium_ spp. [21; 34; 46; 49; 50; 51; 52; 53; 54; 55; 56]. Furthermore, it was described that several microorganisms presenting wild-type-specific amino acids in critical positions of GyrA and/or ParC showed natural resistance to quinolones [57; 58]. In parallel, the role of efflux pumps and impaired permeability was also demonstrated, being considered as responsible for the basal minimal inhibitory concentration (MIC) levels of quinolones and an accessory mechanism of the development of quinolone resistance, when specific mutations lead to down-expression of porins or overexpression of efflux pumps [59; 60; 61; 62; 45; 55; 56]. The role of alterations in quinolone uptake has been considered as the most relevant route of quinolone resistance acquisition only in specific microorganisms, such as _Stenotrophomonas maltophilia_[63; 64], while target mutations seem to play a residual role [64; 65; 66]. Despite the publication of previous unconfirmed or misinterpreted studies [1; 37; 67; 68; 69; 70; 71], the first undoubtable transferable mechanism of quinolone resistance (TMQR) was described in 1998 [39], with different TMQRs being reported in the following years and classified into three main generic mechanisms, quinolone target protection (_qnr_), quinolone inactivation/modification (_aac(6')lb-cr_ and _crpP_) and quinolone pump-out (_qepA_, _aqxAB_ and others), overall accounting for more than 12 different genes and hundreds of allelic  
Figure 1: Subclasses of quinolones. At present, 4 subclasses of quinolones (**A**) quinolines; (**B**) cinnolines; (**C**) Pyridopyrimidine; (**D**) Naphthyridine have been described; atom numeration is described following the quinolines (**A**) structure, with position 1 risen in the nitrogen atom. The figure also illustrates the structure of 2-Pyridons (**E**), because they are structurally related, but at present, none have been introduced in human or veterinary practice. Reproduced from reference [1], with permission from the American Society of Microbiology. variants [1; 72; 73; 74; 75; 76]. Of note, the role of CrpP as a mechanism of quinolone resistance has recently been questioned, and it has been proposed to not consider it among TMQRs [77]. These well-established and largely studied mechanisms of quinolone resistance are referred to as \"canonical mechanisms\" in the present text. The vast majority of studies on quinolone resistance mechanisms, as well as specific thematic reviews, are focused on what was mentioned above [1; 42; 45; 46; 49; 55; 60], while the approaches on acquisition and dispersion of quinolone resistance mostly describe the selection of target mutations as well as the role of mobile (or mobilizable) genetic elements, such as plasmids, transposons, genomic islands, and integrins [1; 44; 76; 78; 79; 80; 81; 82].