<p>Over the past few decades, antibiotic resistance has emerged as a major global health concern and is projected to become the leading cause of mortality worldwide by 2050. The growing human population and global warming are expected to further exacerbate this issue by increasing interactions between humans and pathogenic organisms. Unlike other studies that focus on specific aspects of antibiotic resistance, the aim of this review is to provide a comprehensive overview of this complex topic and to identify the key challenges and unanswered questions arising from heterogeneous data, the lack of scientific consensus on critical definitions, and the widespread dissemination of resistance factors. Priority pathogens identified by the World Health Organization (WHO) are presented to illustrate the clinical manifestations and impact of multidrug-resistant strains. To maintain a consistent narrative throughout the review, two WHO priority pathogens (<i>Haemophilus influenzae</i> and <i>Streptococcus pneumoniae</i>), along with a potential future priority pathogen (<i>Vibrio vulnificus</i>), are used as guiding examples. The bacteria priority pathogens list published by the WHO, and those for fungi, were taken as a starting point for selecting human pathogens. Publications were then selected from Web of Science, PubMed, Scopus and sites of recognized scientific institutions. To include all pathogens with antibiotic resistance, including those not considered as priority by the WHO, <i>V. vulnificus</i> was added because it is already monitored by many international institutions. The selected publications have all been curated to ensure scientific relevance. Molecular aspects of pathogen antibiotic resistance in terms of emergence (e.g. target mutations) and transmission are obviously important factors to consider in the antibiotic resistance issue. Nevertheless, the versatility of definitions related to antibiotic resistance, along with the lack of resources, incomplete datasets, and insufficient standardization of data processing, clearly represent urgent challenges. Furthermore, studies of certain failed public health policies have also highlighted a lack of findings. Identifying challenges linked to antibiotic resistance will enable the scientific community, whether familiar with the subject or not, to understand medical infections issues and exchange ideas more extensively in order to find new innovative pharmacological and non-pharmacological solutions for treating patients. Finally, several diagnostics and therapeutic strategies currently developed for medical applications before 2050 are discussed at the end of this review.</p>