During recent decades, the role of traditional knowledge (TK) in biotechnology development has become increasingly important. The benefits resulting from TK exploration can be tremendous. Due to its significant economic and healthcare contribution to society, the owners of TK (local and indigenous communities) should be sufficiently compensated for the use of their knowledge and their rights on TK should also be properly protected. Contracts are considered to be one of the major means to ensure fair benefit-sharing based on mutually agreed terms between TK users and holders. Contractual agreements are not novel in transactions involving access to genetic resources and benefit-sharing. The most famous and the earliest case was the Merc-INBio agreement. TK has always been only part of such agreements – usually mentioned under prior informed consent – or else it has simply been omitted. Indigenous peoples (or their representatives) have seldom become a party to such contracts. Still, the history of TK exploration revealed several more or less successful cases, where TK holders acted as rightful parties to the associated transfer of the genetic resources. The International Cooperative Biodiversity Group (ICBG) Program was established in 1992 by the National Institute of Health (NIH), the National Science Foundation (NSF), and the U.S. Agency for International Development (later replaced by the Department of Agriculture (USDA)) to run multidisciplinary projects addressing drug development, biodiversity conservation,n, and economic growth. More than a dozen projects in 18 countries in Asia, Africa, and Latin America have been supported under the Program. Seven International Cooperative Biodiversity Groups (awards) are currently being financed. The source of funding in ICBG projects can be from both the public and private sectors. Another essential goal of the Program is “to develop models for sustainable and equitable commercial use of biodiversity-rich ecosystems”. According to the collaboration agreement, bioprospectors obtain access to biological material (including genetic resources) and are required to share benefits derived from the use of these resources and associated TK with suppliers and TK holders. A critical point of the ICBG Program is “the development of ethically sound partnerships among diverse collaboration agreement is verified to comply with the principles of prior informed consent (PIC), access and benefit-sharing (ABS) and several intellectual property rights issues. Each project under ICBG is a kind of “bridge” or a collaborating forum that brings together interested parties for the formulation of an agreement and provides a mechanism for negotiations. The ICBG Program ensures a relatively integrated and successful international licensing scheme of collaboration between indigenous communities, research institutions, and private entities (the U.S., international or multinational), which assists the development of creative potential solutions for anti-biopiracy and efficient exploitation and sustainable use of biological resources and associated TK. An ICBG project usually involves a multinational pharmaceutical corporation, a nongovernmental organization, a research university, and collaborating partners from the source country (research institute, indigenous communities, or their representatives). ICBG projects are characterized by the direct involvement of TK holders or their legal representatives in contractual agreements as rightful parties. Prior informed consent and associated measures are a mandatory part of all ICBG projects. Nevertheless, this article points out the difficulties TK holders and their representatives may encounter and how they can overcome limitations in a contractual arrangement, such as an imbalance of bargaining power and difficulties in enforcement. In the following section, we will address the general structure and main features of the ICBG projects. In the second part of this article, we will discuss three contractual agreements of the ICBG projects, including the Peru-ICBG, Maya-ICBG, and UIC-Vietnam-Laos-ICBG, and address their mechanisms of TK protection. In the third part, we will summarize these three programs. In the fourth part, we will discuss the advantages and flaws of contractual arrangements about TK protection. Finally, we will present our suggestions and solutions.