To gain better insight in the regeneration process responsible for the functional and morphological recovery after acute renal failure (ARF) is one major goal in the field of Nephrology. Results opposing endogeneously produced polypeptide growth factors to be the mediators of this process accumulate. Indeed, the early decrease of renal epidermal growth factor (EGF) and insulin-like growth factor-1 (IGF-1) in different experimental models of ARF has been frequently shown at both the mRNA and protein level, while other growth factors could not be shown to increase. Moreover, the inaccessability of the upregulated receptors for endogeneously produced growth factors, has encouraged research to seek alternative origins for the signals inducing renal regeneration. The accumulation of mononuclear leukocytes in the renal interstitium is a striking observation in renal failure. The existence of a regenerative potential provided by the network of inflammatory mononuclear leukocytes is supported by studies on tissue repair in different fields. This review discusses the infiltrating network of mononuclear leukocytes as a major participant in the regeneration process after acute renal failure, including the approach which can be followed to investigate this hypothesis.