Two human pathogenic mycoplasma species, Mycoplasma pneumoniae and M. genitalium currently pose challenges for the clinical practice.M. pneumoniae is a common cause of community-acquired respiratory infections, which can lead to asymptomatic courses as well as severe atypical pneumonia. Extrapulmonary manifestations also occur. Since December 2023, a strong increase of reported cases has been registered in the federal state of Saxony, where reporting is mandatory. These numbers far exceed those from the previous ten years and are assumed to generally translate to the other federal states. The reason for this development is likely the reduced contact with the pathogen during the COVID-19 pandemic combined with a waning immunity in the population. Although there are no reliable data on an increase in the rate of severe cases, diagnostics and treatment must be adapted. The resistance rate to macrolides (which are primarily used in Germany) remains favorable at approximately 3%.M. genitalium is a sexually transmitted bacterium and is only causally relevant in a portion of male urethritis cases. While its epidemiological significance is limited, resistance to the guideline-recommended antibiotics azithromycin and moxifloxacin is increasing, reaching 69% and 25%, respectively, in samples tested in the German consulting laboratory in recent years. Even higher rates are to be expected in high-risk groups (e.g., men who have sex with men), where M. genitalium is relatively frequent. Under these conditions, therapy can only be successful with a resistance-guided treatment concept.This review summarizes the current state of knowledge on both pathogens.