While true antimicrobial resistance to Chlamydia trachomatis is a rare occurrence, repeat chlamydia infections continue to be reported following treatment with a single 1 g dose of azithromycin or week long doxycycline - with considerable more concern about azithromycin treatment failure. While most repeat positive cases are likely to be reinfections, emerging evidence indicates treatment failure may play a role. Current data suggests that there may are differences in the efficacy of the drugs between rectal and non-rectal sites of infection and factors such as immune response, drug pharmacokinetics, organism load, auto-inoculation from rectum to cervix in women and the genital microbiome may play a role in treatment failure. Other possible reasons for repeat infection include the low discriminatory power of NAAT tests to differentiate between viable and nonviable organisms and failure to detect LGV infection. This review will present the current evidence regarding the management challenges for urogenital and anorectal chlamydia infections and provide some suggestions for where future research efforts are needed to address important knowledge gaps in this area and provide stronger evidence for the development of robust treatment guidelines.