Mantle cell lymphoma (MCL) is characterised by cell cycle dysregulation and a defective DNA damage response pathway. An evolving understanding of these processes has provided the rationale for development of novel agents targeting various steps that appear to be involved in lymphomagenesis and disease progression. Cyclin D1, overexpressed in nearly 100% of MCL, and the cyclin-dependent kinases were among the first rational targets identified. Therapies focusing on the PI3K/Akt pathway, the tumour microenvironment, and cell surface markers are also in various stages of exploration. Here, the authors discuss the rationale for developing targeted therapies and discuss future challenges in combining some of these agents.