Accelerated efforts to end vertical HIV transmission have resulted in a 52% decrease in new infections among children since 2001. However, current approaches to prevent mother-to-child-transmission (PMTCT) assume a linearity and universality. These insufficiently guide clinicians and programmes toward interventions that comprehensively address the varying and changing needs of clients. This results in high levels of loss-to-follow-up at each step of the PMTCT cascade. Current PMTCT approaches must be adapted to respond to the different and complex realities of women, children and families affected by HIV. Drawing on the concept of an 'HIV trajectories,' we screened peer-reviewed literature for promising PMTCT approaches and selected 13 articles for qualitative review when the described intervention involved more than a biomedical approach to PMTCT and mother-child HIV treatment and care. Our qualitative analysis revealed that interventions which integrated elements of the 'HIV trajectories' perspective and built on people living with HIV support/network, community health worker, primary healthcare and early childhood development platforms were successful because they recognized that HIV is an illness, experienced, moderated and managed by numerous factors beyond biomedical interventions alone.On the basis of this review, we call for the adoption of an 'HIV trajectories' perspective that can help assess the comprehensiveness of care provided to women, children and families affected by HIV and can inform the planning and delivery of HIV and related services so that they more adequately respond to the varying needs of clients on different 'HIV trajectories'.