Acute rejection is one of the key factors which determine long-term graft function and survival in renal transplant patients. Timely detection and treatment of rejection is therefore, an important goal in the post-transplant surveillance. The standard care with serum creatinine measurements and biopsy upon allograft dysfunction implies that acute rejection is detected in an advanced stage. Therefore, non-invasive monitoring for acute rejection by markers in blood and urine has been tried over the past decades. This review describes the requirements that should be met by non-invasive markers. The experience with single biomarkers and with newer approaches--mRNA expression analysis, metabolomics, and proteomics--will be discussed, including future directions of necessary research.