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Antimicrobial resistance (AMR) is a growing threat to public health and farming at large. In clinical and veterinary practice, timely characterization of the antibiotic susceptibility profile of bacterial infections is a crucial step in optimizing treatment. High-throughput sequencing is a promising option for clinical point-of-care and ecological surveillance, opening the opportunity to develop genotyping-based AMR determination as a possibly faster alternative to phenotypic testing. In the present work, we compare the performance of state-of-the-art methods for detection of AMR using high-throughput sequencing data from clinical settings. We consider five computational approaches based on alignment (AMRPlusPlus), deep learning (DeepARG), k-mer genomic signatures (KARGA, ResFinder) or hidden Markov models (Meta-MARC). We use an extensive collection of 585 isolates with available AMR resistance profiles determined by phenotypic tests across nine antibiotic classes. We show how the prediction landscape of AMR classifiers is highly heterogeneous, with balanced accuracy varying from 0.40 to 0.92. Although some algorithms—ResFinder, KARGA and AMRPlusPlus—exhibit overall better balanced accuracy than others, the high per-AMR-class variance and related findings suggest that: (1) all algorithms might be subject to sampling bias both in data repositories used for training and experimental/clinical settings; and (2) a portion of clinical samples might contain uncharacterized AMR genes that the algorithms—mostly trained on known AMR genes—fail to generalize upon. These results lead us to formulate practical advice for software configuration and application, and give suggestions for future study designs to further develop AMR prediction tools from proof-of-concept to bedside.