Primary or secondary resistance towards conventional chemotherapeutic agents presents the major clinical obstacle in the induction of remission and definite cure of hematological malignancies. Definition of the underlying molecular mechanisms determining response or resistance not only enables the clinician to define prognostic markers, but moreover, facilitates the design of molecularly targeted therapies aiming to reverse the causative lesion and/or the therapeutic resistance. Prostate-apoptosis-response-gene-4 (par-4), which is expressed in a broad spectrum of normal and neoplastic tissues, was originally described in prostate cancer cells forced to undergo apoptosis. In particular, the observation that overexpression of par-4 potentiates apoptosis in malignant cells while sparing normal tissues, renders the assessment of its biological properties and their potential therapeutic exploitation worthwhile. This article focuses on the functional properties of par- 4 in hematopoietic cells, describing their pro-apoptotic and anti-transforming role, and provides an outlook on the potential therapeutical employment of this knowledge.