In early 2001 there were indications that tuberculosis (TB) was increasingly becoming a problem among drug addicts and homeless persons in Rotterdam, after a periodical screening was discontinued in 1997. A contact investigation around a homeless drug addicted man in Rotterdam with infectious pulmonary TB is described. Contact investigation: A total of 507 drug addicts, homeless persons, and staff of facilities for these risk groups were examined with tuberculin skin testing (TST) and chest radiography. DNA fingerprinting of mycobacteriological cultures through Restricted Fragment Length Polymorphism methodology and molecular epidemiology investigation through cluster analysis were performed. TST showed an infection prevalence of 29%, especially among staff of services for drug addicts and homeless persons. Six persons with active intrathoracic TB were identified. Cluster analysis demonstrated no relation with the initial case but showed intense transmission of TB among drug addicts and homeless persons in Rotterdam by multiple sources. As a consequence of the findings, a proposal to the Council of the City of Rotterdam resulted in the re-introduction of a comprehensive TB screening programme among these risk groups with mobile digital X-ray units (MXUs). This contact investigation gradually obtained the characteristics of a screening of drug addicts and homeless persons. Novel technologies, such as MXUs, facilitate appropriate and efficient outreach approaches to TB control among difficult-to-reach groups. This method and knowledge of individual fingerprints and clusters of TB patients are indispensable for underpinning proposals for change of local TB control strategies and convincing local authorities of the rationale.