Philosophiae Doctor - PhD / South Africa has immensely rich natural flora diversity with more than 20 000 species of higherplants. Asteraceae is one of the biggest families of flowering plants with about 246 genera and 2,300 species in southern Africa. South Africa being home to more than 35 % of the world's Helichrysum species (c.a. 244) of which many are used in traditional medicine, and can be considered as a potential resource for new bioactive chemical entities. Chemical studies on the total extract of the South African Helichrysum species viz: H. teretifolium, H. niveum and H. rutilans resulted in the isolation of twenty eight [14 flavonoids (C1-C10; C22- C25), 10 phloroglucinols (C11-C20) and 4 terpenoids (C21, C26-C28)] pure compounds. The chemical structures of the newly isolated compounds were elucidated on the basis of their 1D and 2D-NMR, HRMS, IR and UV spectroscopic data as heliteretifolin (C1), 1-benzoyl-3-(3-methyl- 2-butenylacetate)-phloroglucinol (helinivene A, C11), 1-benzoyl-3-(2-hydroxyl-3-methyl-3- butene-1-yl)-phloroglucinol (helinivene B, C12) and 8-(2-methyl-1-propanone)-3,5,7- trihydroxyl-2,2-dimethoxychromone (helinivene C, C13), while occurrence of 7- methoxyisoglabranin (C6), 4-methoxyquercetin (C8), 4`-methoxykaempferol (C9), mosloflavone (C10), 3β-24-dihydroxyterexer-14-ene (C21), 5,7,8-trihydroxy-3,6-dimethoxyflavone-8-O-2- methyl-2-butanoate (C22) and 15--hydroxy-(-)-kaur-16-en-19-oic acid (C28), from Helichrysum genus were reported for the first time. In vitro inhibition of oxidative stress by the isolated compounds were measured as total antioxidant capacity using the FRAP, TEAC, ORAC (hydroxyl and peroxyl radicals) as well as Fe2+-induced microsomal lipid peroxidation assays. Inhibitory activities against skin-diseases related enzymeswere evaluated in a tyrosinase and elastase non-biological system, while In vitro prooxidant behavior of the compounds was also investigated in the presence of copper (II). Compounds C7, C8, C11 and C12 in comparison with the commercial antioxidant EGCG demonstrated TEAC (4529.01 ± 2.44; 4170.66 ± 6.72; 19545.00 ± 10.25; 43615.73 ± 6.66; vs 11545.40 ± 17.28) μM TE/g respectively, and ORAChydroxyl radical (7.265 ± 0.71; 6.779 ± 3.40; 64.85± 10.95; 94.97 ± 5.80; vs 3.91 ± 4.65) X106 μM TE/g capacities, respectively. Inhibition of Fe2+- induced microsomal lipid peroxidation demonstrated by C7, C8, C11 and C12 expressed as IC50 values included: 2.931 ± 0.64; 6.449 ± 3.16; 5.115 ± 0.90; 3.553 ± 1.92 µg/mL respectively. Additionally, the total antioxidant capacities measured as FRAP (4816.31 ± 7.42; 3584.17 ± 0.54)µMAAE/g, and ORACperoxyl radical (17.836 ± 2.90; 12.545 ± 5.07) X 103 µMTE/g were also observed for compounds C7 & C8, respectively. Compound C7 demonstrated potent anti-tyrosinase activity with IC50 8.092 ± 7.14, while mild anti-tyrosinase activities were demonstrated by compounds C8, C11, C12, C22 and C23 and expressed as IC50 values (IC50 = 27.573 ± 3.11; 35.625 ± 4.67; 26.719 ± 5.05; 25.735 ± 9.62;24.062 ± 0.61) µg/mL respectively. Anti-elastase activity with IC50 values of 25.313 ± 7.85 µg/mL was observed for C13. This is the first scientific report to be carried out on the chemical and biological profiles of H. teretifolium.H. niveum and H. rutilans. The results suggest that these isolated compounds might become natural agents to inhibit oxidative stress and skin disease-related enzymes, with the prospect of being utilized in cosmetic products formulation upon further biological and clinicalinvestigations.