Antigen presentation by professional antigen-presenting cells (pAPCs) to cytotoxic CD8(+) T cells can occur via two processing routes - the direct and cross-presentation pathways. Cross-presentation of exogenous antigens in the context of major histocompatibility complex (MHC) class I molecules has recently attracted a lot of research interest because it may prove crucial for vaccine development. This alternative pathway has been implicated in priming CD8(+) T-cell responses to pathogens as well as tumours in vivo (cross-priming). In cross-presentation, the internalized antigens can be processed through diverse intracellular routes. As many unresolved questions regarding the molecular basis that controls the cross-priming process still exist, it is essential to explore the various elements involved therein, to better elucidate this pathway. In this review, we summarize current data that explore how the source and nature of antigens could affect their cross-presentation. Moreover, we will discuss and outline how recent advances regarding pAPCs' properties have increased our appreciation of the complex nature of the cross-priming pathway in vivo. In conclusion, we contemplate how the direct and cross-presentation pathways can function to allow the immune system to deal efficiently with diverse pathogens.