Chagas disease (CD), caused by Trypanosoma cruzi, affects millions of people worldwide. Although CD R&D has made progress during the last decade, clinicians and general practitioners are still facing the same challenge, i.e., the lack of adequate markers of clinical cure, hindering assessment of new drug efficacy in clinical trials and counseling of patients about treatment outcome. To date, no new markers have been validated as surrogates of seroreversion-the only marker of parasitological cure which is itself considered to be a surrogate of clinical benefit. T. cruzi DNA detected using PCR cannot currently be considered as a surrogate of seroconversion. Much emphasis has been placed on different T. cruzi antigens but no definite proof of correlation between titers, as determined by serology at a given timepoint, and seroreversion has been shown. Thanks to the improvement of analytical methods and the application of new methodologies, the identification of potential new markers is being facilitated, and some of these are progressing. However, there is a long journey from the identification of a potential biomarker to its clinical validation and acceptance by the regulatory authorities that requires a common effort from the entire Chagas community.