Piperine (PN) and capsaicin (CP) are natural products endowed with antimicrobial, antiviral, anti-inflammatory but most importantly anticancer activity. Cyclodextrins (CDs) are used in pharmaceutical industry to incorporate apolar molecules inside their hydrophobic cavity, increasing the solubility, bioavailability and therapeutic potential of the encapsulated guests. Our recent findings, that indicate more pronounced anticancer activity for PN and CP in their complexed form with parental b-CD and its methylated derivative (DM-b-CD) against two cell lines, impelled us to study their structure in an effort to map the structure-function relationships. In the PN/b-CD inclusion complex, two adjacent hosts form a head-to-head dimer along the a-axis and the guest is ‘axially’ accommodated inside two dimeric cavities. Twenty two waters stabilize the complex units which are arranged in a Channel packing mode. In the PN/DM-b-CD case, PN is hosted inside two successive DM-b-CDs arranged in a head-to-tail mode along the a-axis, with its 1,3-benzodioxole moiety entering the ‘upper’ DM-b-CD and the piperidine ring penetrating the ‘below’ host. In the CP/b-CD case, dimers are arranged along c-axis in an Intermediate mode with the aid of 12 waters and the guest is accommodated inside CDs in a similar to PN’s manner. Finally, in the CP/DM-b-CD case, two distinct monomers in the asymmetric unit form antiparallel channels along the a-axis. The CP’s aliphatic tail is fitted slantwise in host cavity and its vanilloid group is found in the interspace between neighboring hosts.