Syphilis, a curable sexually transmitted infection, has re-emerged as a global public health threat with an estimated 5.6 million new cases every year. Pregnant women and men who have sex with men are key target populations for syphilis control and prevention programs. Frequent syphilis testing for timely and accurate diagnosis of active infections for appropriate clinical management is a key strategy to effectively prevent disease transmission. However, there are persistent challenges in the diagnostic landscape and service delivery/testing models that hinder global syphilis control efforts. In this commentary, we summarise the current trends and challenges in diagnosis of active syphilis infection and identify the data gaps and key areas for research and development of novel point-of-care diagnostics which could help to overcome the present technological, individual and structural barriers in access to syphilis testing. We present expert opinion on future research which will be required to accelerate the validation and implementation of new point-of-care diagnostics in real-world settings.