Lake Nyasa (Lake Malawi) is the world’s ninth largest and third deepest freshwater lake, hosting about 800 to 1000 fish species. However, increased pollution is one of the emerging challenges affecting fish populations. Activities such as coal mining, agriculture, forest burning and deforestation contribute to increased chemical inputs into the lake. Water pollution produces adverse effects such as mortality, inhibited reproduction and growth in aquatic organisms. Consequently, most fish species in the lake are declared by the International Union for Conservation of Nature (IUCN) as threatened, vulnerable, critically endangered or extinct. The effects of contamination can be extended to human health through the food chain and cause various adverse effects. Therefore, it is essential to monitor potential toxicants in the aquatic environment and protect human health. The use of bioindicators to monitor the status of aquatic environments is one of the cheap, effective and easy-to-use options. However, available information on the use of local fish species as a potential bioindicator for risk assessment in Lake Nyasa is limited. This book chapter reports on the usefulness of genetic indices and heavy metal accumulation levels in fish tissues collected along Lake Nyasa as potential tools for health risk assessment.