There are various types of molecular biomarkers that are derived from distinct starting materials. Although many indirect biomarkers are found in blood, their detection remains a challenging issue because of the high degree of fragmentation, minute quantity and a vast amount of non-specific background. The present review points out the sensitivity and specificity of peripheral blood mononuclear cells (PBMCs) as an intact source of biomarkers in a variety of diseases. Multiple recent studies that have used PBMCs as a source of biomarkers reveal the alteration of mRNAs/microRNAs (miRNAs) signature and methylation profile in many kinds of disorders; for instance, dysregulation of mRNAs/miRNAs in schizophrenia, diabetes and different types of cancers and change in the methylation status of LINE-1 in neoplasms. In conclusion with a strong probability, PBMCs mimic conditions of some tissues which are in contact with them like the tumour cells, hence providing a non-invasive and suitable source of biomarkers.