HYPHENATED CHROMATOGRAPHIC SYSTEMS SUCH AS HPLC-DAD, GC-MS AND LC-MS ARE BEING EXTENSIVELY USED FOR DETECTION, QUANTIFICATION AND/OR IDENTIFICATION OF COMPOUNDS IN SAMPLES SUCH AS BIOLOGICAL, ENVIRONMENTAL AND FOOD SAMPLES.HOWEVER, THESE SAMPLES ARE TYPICALLY HAVE A COMPLEX NATURE AND THIS POSES PROBLEMS (SUCH AS BASELINE DRIFT, CO-ELUTION AND OVERLAPPING, PEAK SHIFT BETWEEN SAMPLES AND LOW SIGNAL-TO-NOISE RATIOS) FOR THE TRADITIONAL APPROACHES FOR HANDLING SUCH DATA. ALSO THE NEED FOR REDUCING THE ANALYTICAL TIME THROUGH FAST CHROMATOGRAPHIC RUNS HAS ADDED MORE ANALYTICAL CHALLENGES FOR COMPLEX SAMPLES, TOO. MATRIX EFFECT AS THE MOST IMPORTANT PROBLEM FOR ANALYSIS OF THESE SAMPLES HAS BEEN FACED WHEN THE SAMPLE PREPARATION STEPS ARE NOT SELECTIVE ENOUGH FOR TARGET ANALYTES AND ALSO THE RESOLUTION OF THE ELUTING COMPOUNDS IS NOT PERFECT, TOO. THROUGH RECENT DECADES MANY RESEARCH GROUPS HAVE BEEN USED MORE ELABORATE STRATEGIES SUCH AS SELECTIVE EXTRACTION, EFFECTIVE SAMPLE CLEAN-UP, IMPROVING THE CHROMATOGRAPHIC SEPARATION AND SUITABLE CALIBRATION APPROACHES, E.G., THE USE OF MATRIX-MATCHED STANDARDS TO COMPENSATE THE MATRIX EFFECT [1-3]. HOWEVER, MANY OF THESE STRATEGIES MAY BE TIME-CONSUMING AND SHOULD BE SPECIFIC FOR EACH REAL SAMPLE THROUGH THIS FACT THAT THE INTERFERENCE EFFECT IS COMPLETELY MATRIX DEPENDENT. IN FACT, IN MANY SITUATIONS ALTHOUGH THE ENRICHMENT AND CLEAN-UP STEPS WERE CAREFULLY OPTIMIZED, THE SAMPLE MATRIX STILL CAUSED A LARGE BASELINE DRIFT, AND ALSO ADDITIVE INTERFERENCES WERE PRESENT AT THE RETENTION TIME REGION OF THE ANALYTES.MULTIWAY CALIBRATION METHODS SUCH AS GRAM, PARAFAC, PARAFAC2, ATLD, SWATLD, TUCKER3, MCR-ALS, U-PLS/RBL, N-PLS/RBL AND ANN/RBL WITH EXPLOITING SECOND-ORDER ADVANTAGE HAVE BEEN USEFUL ALTERNATIVES FOR DETECTION AND QUANTIFICATION OF ANALYTES IN COMPLEX REAL SAMPLES AND IN THE PRESENCE OF UNCALIBRATED AND UNKNOWN INTERFERENCES [1]. SO THESE TECHNIQUES CAN BE VERY USEFUL AND PROMISING TOOLS TO ENHANCE THE ANALYTICAL PERFORMANCE OF CHROMATOGRAPHIC SYSTEMS. IN THIS WAY, THE MOST COMMON THREE-WAY TECHNIQUES AND RECENTLY DEVELOPED STRATEGIES USED IN SECOND-ORDER CALIBRATION FOR HYPHENATED CHROMATOGRAPHIC DATA AND SOME NECESSARY SIGNAL-PRETREATMENT STEPS WITH A FOCUS ON OUR RESEARCH WORKS IS DEMONSTRATED.