Among lesions with in-stent restenosis (ISR), the in-stent chronic re-occlusions (ISR-CTO) is a subset with particularly unfavourable features regarding both the repeat procedure success and the prevention of lesion recurrence. A review of the literature and personal databases reveals that the prevalence of complete occlusive ISR represents about 5-10% of all CTO lesions, with little evidence regarding the successful long-term treatment. In fact, these lesions had been excluded from large contemporary trials dealing with the best modality for ISR management, and which showed eventually the superiority of drug-eluting stents (DES) as compared to brachytherapy. Only a limited experience exists with brachytherapy for ISR-CTOs, showing an inferior outcome as compared to non-occlusive ISRs. The lack of large study experience is true also for DES, so that only anecdotal experience in small series of patients is available. In some of the recent studies of DES in CTOs, again, ISR-CTOs were not included. Our own experience shows a slightly lower primary success rate of about 70% in ISR-CTOs as compared to 85% in primary CTOs, with a slightly higher recurrence rate with DES of 25%. ISR-CTOs are a clinical problem that had not been systematically addressed. However, we hope that this lesion subset may be of less relevance in the future when the use of DES in lesions which are prone for lesion recurrence will lead to less diffuse and occlusive ISR, and leaves rather focal and better manageable recurrent lesions.