Clinicians are facing unexpected issues in everyday practice, and these may become counterintuitive or challenging. Illustrative examples are provided by the hypersensitivity to universally used immunosuppressants such as corticosteroids or antibiotics such as beta-lactam. Secondly, additional issues are represented by the discovery of new pathogenetic mechanisms involved in rheumatoid and psoriatic arthritis or other chronic inflammatory diseases, genomic susceptibility to enigmatic diseases such as giant cell arteritis, or the shared role of specific mediators such as semaphorins. Third, the therapeutic armamentarium has dramatically changed over the past decade following the introduction of biotechnological drugs, and new mechanisms are being proposed to reduce adverse events or increase the drug effectiveness, particularly on cardiovascular comorbidities. Finally, rare diseases continue to represent difficult cases, as for Cogan's syndrome, with limited literature available for clinical recommendations. For these reason, the present issue of Clinical Reviews in Allergy and Immunology is timely and dedicated to these and other unique topics in clinical immunology and allergy. The aim of this issue is thus to help clinicians involved in internal medicine as well as allergists and clinical immunologists while discussing new pathways that will prove important in the near future.